Archive for the ‘Compound Screening’ Category
Nigeria: FG and Cost of Cancer Screening
Last Updated on Monday, 28 November 2011 02:03 Written by admin Monday, 28 November 2011 02:03
THE Federal Government’s recent directive to its hospitals to reduce the cost of cancer screening, though very commendable, is long overdue, considering that late diagnosis of the disease has resulted in the high rate of cancer related deaths in the country.
Cancer is one of the leading causes of deaths in the world, especially in developing countries, which carry about 80 per cent of the burden, globally. Unfortunately, in Nigeria with over 160 million people, going by the latest global report on population, detection of the killer non-communicable disease (NCD) is usually late.
Minister of Health, Prof. Onyebuchi Chukwu, who announced the reduction in the cost of screening for breast, cervical, prostate and colon cancers during the recent 17th Annual Conference of the Nigerian Association of Urological Surgeons (NAUS) in Abuja, said the directive to provide screening services at affordable prices is to ensure that the disease is detected early.
Other measures being taken by government to tackle the cancer scourge, he said, include equipping fully the University of Port Harcourt Teaching Hospital, the Federal Medical Centre, Gusau, Zamfara State and the Vesico Virginal Fistula (VVF) Centre, Abakaliki, Ebonyi State with mammography machines, cryoprobes, video culposcopes, ultrasound, loop electrosurgical excision procedure and enzyme-linked immunosorbent assay machines, so that these institutions can serve as referral centres for those who screen positive for pre-malignant lesions.
With the World Health Organisation (WHO) projecting that about 84 million people may die of cancer by 2015 if urgent steps are not taken to arrest the scourge, there is, indeed, need to facilitate a national policy on cancer management, starting with free or significantly reduced cost of cancer screening.
These moves by the Federal Government are steps in the right direction, considering that cancer is one disease that is no respecter of social status and one that has continued to deal devastating blows on the productive segments of the nation’s economy.
Among notable Nigerians whose lives were cut short by cancer are human rights activist and lawyer, Chief Gani Fawehinmi, who died in 2009 after a prolonged battle with lung cancer, Dr. Bekolari Ransome-Kuti, a medical doctor and human rights activist and Yemi Tella, coach of the Nigerian 2007 FIFA U-17 World Cup winning team.
Maryam, wife of former military president, Gen. Ibrahim Babangida, died of ovarian cancer on December 27, 2009 at California’s City Hope Hospital in the United States, aged 61, while the wife of Edo State Governor, Adams Oshiomhole, was swept away by cancer of the breast.
Presently, about two million cancer cases are said to be recorded in Nigeria with an estimated 350,000 new cases being diagnosed annually. Of the two million, only 10 per cent or about 200,000, have access to hospitals with radiotherapy facilities, while out of the number, only five per cent, about 10,000, have the resources to go abroad where they pay between $10,000 and $15,000 per patient for a three to five-weeks course of radiotherapy.
While about 27 per cent of the two million cases are suffering from breast cancer, about 25 per cent are cancer of the cervix cases. And of these two cancers that are devastating women in Nigeria, one has good prognosis, if detected early, while the other can be prevented. Yet they continue to cause untold hardships and deaths simply because of the dearth, and high cost, of facilities, especially for early detection, among other constraints.
Nigeria’s mortality and morbidity statistics for cancer are said to be high due to the late presentation syndrome involving 83-87 per cent of cancer patients, simply because the awareness level of Nigerians, especially women, is very low, even as this is dogged by superstition and cultural restraints.
As a matter of fact, some medical experts have argued that even the estimated 350,000 new cases of cancer diagnosed annually in Nigeria is far from the true figure of the cancer crisis in the country, insisting that a large number of cancers are not detected as majority of Nigerians are poor and live in rural areas, far removed from health facilities.
Lack of, or inadequate, research into this debilitating disease is also a major challenge. Nigeria, for instance, is said to contribute little or nothing to the global body of literature on cancers and most of these contributions are hospital based, perhaps representing the tip of the iceberg as majority of Nigerians live in rural areas, unable to access any health facilities.
As such, the cancer awareness efforts and screening methods to enhance early detection do not seem to have had much impact on the nation.
No doubt, the problems of lack of access to quality health care, ignorance, poverty and poor co-ordination of issues of health education complicate issues. For instance, facilities such as computerised tomography (CT) and Magnetic Resonance Imaging (MRI) are difficult to come by, and when available, the cost of accessing such facilities put them out of reach of the average citizen.
Of more concern is the fact that clinical services for cancer are grossly inadequate and poorly distributed. Only a few centers have functioning radiotherapy equipment, and though radiologic services are said to be generally available, access is seriously limited by high cost.
So, while the Federal Government’s move to reduce the cost of cancer screening in federal hospitals is commended, we call on the authorities to ensure that the screening equipment are available and more easily accessible, especially in the rural areas, while a more vigorous and better co-ordinated effort into cancer research must be encouraged in institutions across the country.
Source: http://allafrica.com/stories/201111241060.html
Posted under Africa, Cancer Research, Compound Screening, Genetics & Pharmacogenetics, HT Screening, Medicinal Chemistry, Oncology Research, Press Releases, R & D, Reports | Comments Off
NMR Fine-Tuned for High-Content Metabolomics Screening
Last Updated on Monday, 28 November 2011 01:48 Written by admin Monday, 28 November 2011 01:48
Scientists report on the development of a nuclear magnetic resonance (NMR)-based method forscreening the metabolomic response of drug-treated mammalian cells to drug therapy. TheSanford-Burnham Medical Research Institute, and Rady Children’s Hospital investigators, say the highly sensitive, fast, and simple method is carried out in 96-well format, and could have particular utility as a method for high-throughput primary screens. The preparation technique takes just five minutes to metabolically inactivate and lyse hundreds of drug-treated samples, and a metabolomic screening of around 100 samples can be carried out in 24 hours.
Giovanni Paternostro, M.D., and colleagues describe their approach, analyze the results of validation studies on drug-treated cancer cell lines, and evaluate the technique for screening a kinase inhibitor library. Their work is described in Nature Communications in a paper titled “Metabolomic high-content nuclear magnetic resonance-based drug screening of a kinase inhibitor library.”
High-throughput screening (HTS) is widely used as a tool in drug discovery, but most screens monitor a single variable, which is often related to activity on a single target, the researchers explain. Although high-content screening (HCS) approaches that provide multivariate readouts are gaining ground, these techniques generally rely on automated digital microscopy.
The technique developed by the Sanford-Burnham researchers involves seeding cells into a 96-well plate and treating them with several drugs. The cells’ metabolism is then quenched using sodium dodecyl sulphate (SDS), and the cells lysed using ultrasonication, in an overall process that takes just five minutes. The entire content of the well, including endo- and exo-metabolome, is then transferred into an NMR tube for analysis.
The team needed to address the relative contribution of the intracellular metabolome to the NMR spectrum acquired on the well content, including both medium and the lysed cell metabolomes. To answer this they generated NMR spectra on the entire content of the well (i.e., both endo- and exo-metabolomes), and also on the exometabolome, the endometabolome, and the medium. They found that major NMR signals arose from the extracellular metabolites, but several signals arising from the intracellular metabolites were also detected, for example glutamate, choline, and phosphocholine. Importantly, they found that spectra acquired on samples containing both endo- and extracellular metabolomes included signals resulting exclusively from the endometabolome—such as phosphocholine and glycerophosphocholine—which didn’t overlap with other extracellular resonances.
The researchers evaluated the sensitivity of the approach for monitoring metabolic changes induced by 24 hours of drug treatment, on both suspension (CCRF-CEM human leukemia cells) and adherent mammalian carcinoma cell lines (human SKOV-3 ovarian cancer cells). The cell lines were treated using either dexamethasone (Dex), rapamycin (Rap) dichloroacetate (DCA), vincristine (Vin), and different doses of L-asparaginase. The resulting spectra, generated using three different 1H NMR pulse sequences, showed that, as expected, the response to drug treatment by the more resistant SKOV-3 cells was far less pronounced compared with the CCRF-CEM cells. Encouragingly, the NMR screening approach could also be applied to detecting metabolic changes in response to forms of intervention, such as the transfection of HeLa cells the microRNAs mir-121 and mir-16. These results indicated that mir-16 induced a greater degree of metabolomic change than mir-121.
Because the developed technique requires just a small amount of cells, the investigators suggest in might have utility in studying drug response directly in primary cells, and so avoid phenotypic changes that can be induced by growth in culture. They evaluated metabolomic changes in cells isolated from bone marrow specimens of an untreated AML patient, in response to treatment with Rap and L-asparaginase, at different doses. In order to specifically highlight metabolic changes in the cells themselves, the NRM spectra acquired on unconditioned medium were compared to those acquired on AML primary cells with and without drug administraton. The resulting spectra clearly showed distinct changes in the metabolome of the primary cells as a result of drug treatment. Further analyses indicated these changes were more pronounced in response to L-asparaginase than for Rap therapy.
The team then moved on to use the approach for carrying out screening of metabolomic response to a kinase inhibitor (KI) library. Multiple rounds of screening on KIs with well-characterized and less well-characterized effects on the metabolome confirmed the utility of the technique for identifying metabolic alterations resulting from inhibitor treatment. More specifically, four hits were validated from their action on the well-characterized lactate to pyruvate ratio parameter.
“We believe that this NMR-based assay might find an immediate relevant application for screening a large number of individual or combinatorial drug interventions, reducing the number of possible drugs to be studied in more detail,” the authors state. “In addition, it might find an immediate relevant application into clinical studies.”
They admit that the main drawback of NMR is the relatively limited number of compounds that can be detected. However, they stress, “although not comprehensive of all metabolites, the wealth of information obtained from the multivariate metabolic readout is of great advantage for drug screening purposes.” The method could therefore represent a valuable high-throughput primary screen, which could then be followed by secondary assays to analyze the exo- and endo-metabolomes of selected hits using combinations of different anaytical platforms.
“There are many other possible applications of this method, for example lactate production and substrate utilization in cancer versus noncancer cells, or gluconeogenesis from different substrates in hepatocytes, relevant to diabetes. Importantly, because the measurements are performed within a global metabolic profile, they can also provide a series of compounds with partially different mechanisms of actions, which can be explored for potential synergies.”
Source: http://www.genengnews.com/gen-news-highlights/nmr-fine-tuned-for-high-content-metabolomics-screening/81245988/
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Fragment Library
Last Updated on Monday, 20 December 2010 02:59 Written by Editor Monday, 20 December 2010 02:59
Thermo Fisher Scientific Inc. announced that its Maybridge Ro3 Diversity Fragment Library has helped researchers validate an emerging technique for drug discovery that targets key protein receptors involved in a wide range of biological functions.
David Myszka, founder of Biosensor Tools LLC and director of the Center for Biomolecular Interaction Analysis at the University of Utah, used surface plasmon resonance (SPR) to screen small molecules (fragments) in the Maybridge Ro3 collection against stabilised G-Protein Coupled Receptors (GPCRs) provided by Heptares Therapeutics1. Several new classes of compounds were identified from the Ro3 library, which is accelerating drug discovery efforts around these receptors
Dr. Myszka’s study demonstrated for the first time that fragment screening by SPR is an effective approach. It utilises the sensor surface to purify and concentrate solubilised tagged GPCRs and then characterise their binding activities with the fragments. Dr. Myszka and Rebecca Rich, a research scientist in Dr. Myszka’s group, recently presented their work, “Fragment Screening against Membrane Receptors using SPR,” at the Fragment-Based Lead Discovery Conference in Philadelphia and at the Developments in Protein Interaction Analysis symposium in Barcelona, Spain.
“While fragment screening by SPR has become standard practice, this is the first example of a successful SPR-based fragment screen against GPCRs,” said Dr. Myszka. “One major factor contributing to our success was the integrity of the Maybridge Ro3 Fragments. The library was well-behaved in terms of high solubility and displayed minimal nonspecific binding or so-called promiscuous binders. In addition, the structural diversity within this library allowed us to span a lot of chemical space, helping us to identify subsets of novel compounds that targeted two GPCRs. From the primary screen we identified thematic structural elements in the hits and then selected analogs from within the full Maybridge collection to investigate as confirmatory hits. With these follow-up studies in hand, we are now poised to pursue the next stage in elaborating compounds for drug development.”
“The guaranteed aqueous solubility of Maybridge Ro3 Fragments is not only key from a practical perspective, but it also provides an insight into likely ADME problems as the hits are evolved into drug-like molecules,” said Simon Pearce, product manager for Maybridge products at Thermo Fisher Scientific. “Furthermore, pharmacophoric enrichment and quality assurance of at least 95 percent, with full Rule of Three (Ro3) compliance, meant that all fragments used for the study possessed physicochemical properties that also increased the probability of successful hits.”
Thermo Fisher Scientific and Dr. Myszka are continuing their collaboration as the study now expands to drug development using additional Maybridge Ro3 Fragments.
Source: Thermo Fisher Scientific, Inc and DDDMag.com
Posted under Compound Libraries, Compound Screening, Diversity Libraries, Drug Development, Europe, Europe, North America, Press Releases, USA and Canada | Comments Off
Jet Lag Pill to Slow Down Body Clock
Last Updated on Thursday, 16 December 2010 10:57 Written by Editor Thursday, 16 December 2010 10:57
Scientists are one step closer to developing a jet lag pill that could relieve millions of long-haul passengers from sleepless nights and mid-afternoon drowsiness.
Using automated screening techniques developed by pharmaceutical companies to find new drugs, researchers from UC San Diego and three other research institutions have discovered a molecule with the most potent effects ever seen on the biological clock.
Dubbed “longdaysin,” for its ability to dramatically slow down the biological clock, the new compound could pave the way for a host of new drugs to treat severe sleep disorders or quickly reset the biological clocks of jet-lagged travellers who regularly travel across multiple time zones.
The researchers demonstrated the dramatic effects of longdaysin by lengthening the biological clocks of larval zebra fish by more than 10 hours.
“Theoretically, longdaysin or a compound like it could be used to correct sleep disorders such as the genetic disorder Familial Advanced Sleep syndrome, which is characterized by a clock that’s running too fast,” said Steve Kay, dean of UCSD’s Division of Biological Sciences, who headed the research team.
“A compound that makes the clock slow down or speed up can also be used to phase-shift the clock—in other words, to bump or reset the hands of the clock. This would help your body catch up when it is jet lagged or reset it to a normal day-night cycle when it has been thrown out of phase by shift work.”
Biologists in Kay’s laboratory and the nearby Genomics Institute of the Novartis Research Foundation, led by Tsuyoshi Hirota, the first author of the paper, discovered longdaysin by screening thousands of compounds with a robot that tested the reaction of each compound with a line of human bone cancer cells that the researchers genetically modified so they could see visually the changes in the cells” circadian rhythms.
This was done in the cells by attaching a clock gene to a luciferase gene used by fireflies to glow at night, so that the cells glowed when the biological clock was activated.
The robot screened more than 120,000 potential compounds from a chemical library into individual micro-titer wells—a system used by drug companies called high-throughput screening—and automatically singled out those molecules found to have the biggest effects on the biological clock.
Once Kay’s group had isolated longdaysin, they turned to biological chemists in Peter Schultz’s laboratory at The Scripps Research Institute to characterize the molecule and figure out how it lengthened the biological clock.
That analysis showed that three separate protein kinases were responsible for the dramatic effect of longdaysin, one of which, CK1alpha, had previously been ignored by chronobiology researchers.
The researchers then showed that longdaysin had the same effect of lengthening the biological clock in mouse tissue samples and in zebrafish larvae that carried luciferase genes attached to their clock genes.
Kay’s research team plans to test longdaysin on mice in the near future, but their goal isn’t to develop longdaysin into a drug. “Longdaysin is not as potent as we would like,” he adds. “This will be a tool for research.”
Source: The Times of India http://timesofindia.indiatimes.com/life-style/health-fitness/health/Jet-lag-pill-to-slow-down-body-clock/articleshow/7104145.cms#ixzz18HqNJo62
Posted under Cell Analysis, Compound Libraries, Compound Screening, Discoveries, Innovations and Patents, Drug Development, Research Projects | Comments Off
Virtual Screening
Last Updated on Monday, 11 October 2010 09:46 Written by Editor Monday, 11 October 2010 09:46
1. Description
1.
Virtual screening (VS) can be a useful alternative to HTS, especially if the assay will only permit a relatively small number of compounds to be tested. Different methods can be used depending on the information available. For any virtual screening, the selection of the database is as important as the methods used.
2.
The number of compounds tested is also critical to the ability to identify hits. A typical HTS needs on the order of 5000 compounds to identify a single hit. Expecting virtual screening to reliably identify a hit in ~50 compounds is optimistic. This can usually only be successful when a great deal is known about the binding site, or a ligand series is already identified. A more reasonable expectation would be to test a few hundred compounds to identify (and confirm) a few good hits.
3.
Follow-up of VS hits typically follows a similar procedure to HTS follow-up as a great deal of additional information can be obtained by testing related compounds.
4.
In the absence of a target protein crystal structure, VS can be done based on the ligand conformation, either through a pharmacophore search (if a series of ligands is known) or by a shape-based method if a single (or few) ligand is known. This method compared database ligands to the 3D shape of the surface of the query molecule. Those compounds that most closely match the query shape (and chemical nature) are the highest ranked. In cases where the ligand conformation is extracted from a crystal structure, this approach can be as good as docking to the protein directly.
5.
When a crystal structure of the target protein is available, VS is commonly done by high-throughput docking and scoring. The goal of this docking is not necessarily a highly accurate biding mode, but instead is a list of compounds that is likely to bind to the target. The docking algorithms used may therefore be different from those used for detailed docking and scoring. This approach is typically slower than ligand based VS methods.
2. Requirements
1.
•Ligand VS: single known ligand, ideally with known or predicted binding conformation
2.
•Pharmacophore: several ligands known to bind to the same target binding site
3.
•Structure VS: crystal structure, ideally with ligand or natural substrate bound
3. Limitations
1.
•Significant number of compounds must still be tested to obtain a hit
2.
•Choice of database often determines the quality of hits
4. Deliverables
1.
•Ranked list of compounds (available for purchase) for testing
2.
•Prediction of binding mode (if structure or pharmacophore is developed)
Source: biochem.wustl.edu
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An automated screening method for drugs and toxic compounds in human serum and urine using liquid chromatography–tandem mass spectrometry
Last Updated on Monday, 11 October 2010 09:44 Written by Editor Monday, 11 October 2010 09:44
Stefan Sturma, Felix Hammannb, Juergen Dreweb, Hans H. Maurerc and André Scholera, Corresponding Author Contact Information, E-mail The Corresponding Author
a University Hospital of Basel, Laboratory Medicine, Clinical Chemistry Laboratory, Petersgraben 4, CH-4031 Basel, Switzerland
b University Hospital of Basel, Clinical Pharmacology and Toxicology, Basel, Switzerland
c Saarland University, Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Homburg/Saar, Germany
Received 30 January 2010;
accepted 14 August 2010.
Available online 21 August 2010.
Abstract
A fully automated screening using liquid chromatography–mass spectrometric method applying data-dependent acquisition was developed to identify toxicologically relevant substances in serum and urine. A library including more than 405 spectra of about 365 compounds (main drugs and important metabolites) was established. An easy to use program was created to automate and accelerate library search. Drugs were identified based on their relative retention times, molecular ions and fragment ions. Limits of detection were tested with 100 of the 365 compounds the majority of these were lower than 100 ?g/l (67%). The developed LC–MS–MS system seems to be a valuable alternative to other general unknown screening methods allowing fast and specific identification of drugs in serum and urine samples.
Keywords: General unknown screening; Data-dependent acquisition; Toxic compounds
Abbreviations: GUS, general unknown screening; APCI, atmospheric pressure chemical ionization; MS–MS, tandem mass spectrometry; nd, not detected; LOD, limit of detection; DAD, diode array detection; CID, collision induced dissociation; DDA, data-dependent acquisition; SPE, solid-phase extraction; IS, internal standard; PE%, process efficiency in percent; RRT, relative retention time; RT, retention time
Article Outline
1.
Introduction
2.
Experimental
2.1. Materials
2.2. Apparatus
2.3. Methods
2.3.1. Standard solutions
2.3.2. Extraction procedure
2.3.3. Evaluation of matrix effects and process efficiency
2.3.4. Liquid chromatography
2.3.5. Mass spectrometry
2.3.6. Evaluation of the limit of detection (LOD)
2.3.7. Mass spectral library
2.3.8. Mass spectral library search program (XcLibraryScreening)
3.
Results and discussion
4.
Conclusions
Appendix A.
Supplementary data
References
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Molecular Target for Screening: G-Protein-Coupled Receptors
Last Updated on Friday, 20 August 2010 06:48 Written by Editor Thursday, 19 August 2010 03:10
Newark, DE. August, 2010 – Press Release – TimTec, LLC. – Molecular Target for Screening: G-Protein-Coupled Receptors, ActiTarg-G
G-Protein-Coupled Receptors are the largest gene families in the human genome and, rightfully so, have become the leading molecular target in 2008. In 2009 SBS April meeting in Lille, France, followed-up with screening trends report stating that “GPCRs are expected to replace protein kinases as the most common molecular target used by HTS laboratories.”
GPCRs are the largest family of cell surface receptors being integral to the number of cellular and physiological functions, including light sensing, smell, appetite control, insulin secretion, and blood pressure modulation. These receptors generally have a seven-membrane spanning alpha-helical topography, and while these receptors are similar in overall structure and function, they differ in key amino acid residues. The potential for this super family of receptors to reveal small molecule modulators of a significant biological function has been responsible for the focus of intense drug discovery efforts.
TimTec GPCR Ligands library is called ActiTarg-G. It currently counts 2,300 molecules available in various formatting options, and can be delivered in vials or in 96 or 384-well plates. ActiTarg-G is the set of diverse molecules that contain chemical lattices present in compounds reported in the technical or patent literature to possess GPCR-ligand properties.
Contact Information to schedule free consultation:
TimTec LLC
Harmony Business Park A-301
Newark DE 19711
Tel 302 292 8500
Fax 302 292 8520
Web: http://www.timtec.net/news/timtec-news/actitarg-g-gpcr-ligandshtml.html
About TimTec
TimTec LLC is a privately held company located in Newark Delaware, USA. It was founded in 1995 and began its work in the areas of acquisition and distribution of synthetic organic and natural compounds and collections, custom synthesis, and laboratory equipment to become a full service partner for drug discovery. TimTec has established a global network of thousands of scientists from research centers around the world. International customers include major pharmaceutical, biotech, agricultural, and educational companies and institutions, which use TimTec products for research and development programs.
Posted under Compound Libraries, Compound Screening, Genomics & Pharmacogenomics, North America, Press Releases, Targeted Libraries | Comments Off
Screen for molecules that inhibit formation of A-beta oligomers
Last Updated on Thursday, 5 August 2010 02:00 Written by Editor Thursday, 5 August 2010 02:00
Alzheimer’s disease (AD) is a devastating neurological disorder characterized by the deposition of aggregated proteins in the brain in the form of extracellular beta-amyloid in senile plaques and intracellular tau in neurofibrillary tangles. A current approach towards treatment of Alzheimer’s disease is by using inhibitors of amyloid beta aggregation. Current screening protocols for inhibitors of amyloid beta aggregation generally involve first using assays for fibers, e.g, thioflavin T binding to detect inhibition of fiber formation or fiber disassembly, and the compounds uncovered in these screens are then examined for effects on oligomer formation. This approach for screening compounds having amyloid beta aggregation inhibition properties is an indirect one, but is used because oligomers do not bind thioflavin T and there is no easy assay for their appearance. A compound which only inhibits oligomer formation, but does not inhibit protective fiber growth would never be detected by this indirect approach. The present UIC invention overcomes these deficiencies and provides an easy and direct assay in yeast for high-throughput screening of compounds that can inhibit amyloid-beta oligomer formation but does not inhibit protective fiber growth.
Description/Details
The present UIC invention is directed towards a yeast high-throughput screen for detecting compounds that inhibit amyloid-beta aggregation. It also provides a yeast in vivo assay for amyloid-beta aggregation. The assay involves replacing the N-terminus of the translational release factor, Sup35, with Abeta-42mer, and examining the activity of said construct in an ade1-14 yeast strain in which the normal Sup35 gene was deleted, and inhibition of release factor translation termination activity of the fusion construct can be assayed for growth on –Ade medium.
Applications
Screening for compounds that inhibit amyloid-beta oligomer formation
Benefits
• Easily detects compounds that inhibit amyloid-beta oligomer formation but do not inhibit protective fiber growth Selects compounds with more “drug-like” properties (e.g., membrane permeability and cytotoxicity effects) compared to biochemical HTS screens, Clean read-out against a null background in a heterologous, yet eukaryotic environment, compared to mammalian cells, Self-renewal system, Simple handling, Fast discrimination of real hits from false positives, Inexpensive culture conditions
source: otm.illinois.edu
Posted under Alzheimer's disease, Compound Screening | Comments Off
The NIH Molecular Libraries Program: Identifying Chemical Probes for New Medicines
Last Updated on Saturday, 24 July 2010 04:24 Written by Editor Monday, 12 July 2010 02:12
Alice McCarthy
In 2003, several program leaders within the National Institutes of Health (NIH) recognized that the results from the recently completed Human Genome Project were a launching pad for further study. Now that scientists knew the genome, how could they determine gene function? In particular, how could scientists find specific biological pathways and targets that could lead to new advances in biology and new drug therapies?
MLP was founded to fund research spanning multiple NIH institutes, all with one goal: identify new chemical probes to explore new targets for drug therapies.
The Molecular Libraries Program (MLP), an NIH Roadmap Initiative first funded in 2004, has partially answered those questions. “At the time the term ‘chemical genomics’ was on the minds of NIH researchers,†explains Carson Loomis, Ph.D., Program Director, Molecular Libraries. “The human genome was available and it was agreed that the NIH should become more involved in screening new small molecules to get better targets.†The pharmaceutical industry had become frustrated by drug failures in development lacking the means to sufficiently validate potential targets. “They were at the breaking edge of science, yet when a new kinase was discovered and they developed a drug for it, it would often fail,†explains Loomis. “The feeling was that we needed more basic research and that the NIH needed to further this cause of validating targets.â€
The act of Congress creating the MLP now includes the efforts of nine Molecular Libraries Probe Production Centers. They include one intramural NIH site, the National Center for Chemical Genomics (NCGC), and eight extramural sequencing and screening centers: the Broad Institute, the Sanford-Burnham Medical Research Institute, Johns Hopkins University, Scripps Research Institute, the University of New Mexico, Southern Research Institute, the University of Kansas, and Vanderbilt University.
The common purpose of these probe production centers is to generate new small molecule chemical probes by performing high throughput screening, secondary screens, and medicinal chemistry. The biological assays for these probes are sourced from the scientific community at large.
MLP was founded to fund research spanning multiple NIH institutes, all with one goal: identify new chemical probes to explore new targets for drug therapies.
Screening Library
The workhorse of the MLP program is its 350,000-strong library of unique chemical structures of the NIH’s Molecular Libraries Small Molecule Repository (MLSMR). The MLSMR is screened with biological assays or bioactivity experiments looking for particular areas of biological activity.
Small molecule probes can be targeted to interact with extreme precision with a cell or cell byproduct. This specificity provides useful details about the steps in a cell’s function and ultimately to its disease pathway. A “true positive active†compound found to be active against a biological target is classified as a chemical probe.
As part of the MLP mandate, all identified probes are immediately reported to the National Library of Medicine’s PubChem, a chemical and biological activity repository. Full results may be withheld for up to year to allow investigators to publish their findings.
Though only 350,000 of the 26 million unique chemical structures found in PubChem derive from the MLP, they have generated a wealth of information when combined with the biological assays also deposited. Each participating MLP center receives the screening library and uses it to test a variety of biological questions. “The result is that over 90 million unique biological results have been placed in PubChem from the MLP sites, representing over 80% of the total,†explains Steve Bryant, Ph.D., Program Director, PubChem. “It’s the combination of the screening library with the unique bioassays that provide the information that lead to the designation of probe.â€
All of the centers deposit the entire screening experiment, even if most of the results showed no activity or low activity. “It’s important to know what doesn’t work as well as what does,†explains Bryant.
Before victory is proclaimed, however, a probe has to be validated. Enrique Michelotti, Ph.D., who oversees this process within the MLP, says, “The assays and the probes identified have to address a very specific problem in biology.†Assay providers need to supply the proposed assay to NIH for peer-review. The network runs the assay through high throughput screening against the 350,000 compound MLSMR collection. “Any new compound that is active in that assay is followed up by chemistry and has to be best in class in that it is addressing some particular issue in biology,†he says. “That is what we are looking for in a probe.â€
One hundred fifty validated probes have been created since the $70 million, 4 year production phase of the effort began in 2008, but only about 120 are publicly available due to the 1 year embargo. Full details on the available probes can be found at the MLP website (http://mli.nih.gov/mli/).
Screening, Et Al.
The data coming from the MLP includes information on the chemical structures as well as the assays and analytical tools regarding bioactivity.
“This lends real value to the program because each center in the MLP has a particular area of expertise regarding types of assays used or areas of research,†says Loomis.
But the MLP includes a bit more than small molecule screening. It also funds technology development encompassing new instrumentation, chemical diversity efforts including natural products methods, and pilot scale libraries to generate novel new compounds to put into the screening library. For example, researchers at the University of New Mexico, an MLP center, are adapting flow cytometry to high throughput screening.
Probe = Research Tool
MLP defines a probe as a compound that can be useful as a research tool. “It does not have to work in animals but ideally it will work in cells,†explains Loomis. “It could be a biochemical assay looking for a means to block a compound’s phosphorylation ability, or phenotypic assays.†The latter are of very high value to the MLP because these screens might point the way in finding a better target for a pathway.
The MLP emphasizes rare and neglected diseases, but they cover a large range of therapeutic areas including cancer, inflammation, infectious disease, and metabolic diseases. However, MLP funding is limited to the probe discovery process only. “If, with a little more study, some of these probes are found to be useful in animals and eventually becomes a lead for chemistry to develop a drug, that is a win/win for us, but our funding won’t go that far,†adds Loomis. If a probe discoverer believes it may represent a great opportunity for drug development, alternative funding is necessary.
“In my view, the most interesting and valuable part of the MLP program is the number of assays we have spanning multiple therapeutic areas or potential targets,†says Michelotti. In MLP, the assays are designed in a way to capture multiple levels of biological activity. “They also include information on potential roles of agonists, antagonists, partial agonists, etc., as the information we receive is denser, more rich, because it is not limited to one particular target.†And even within one target, Michelotti points out that the biological information is more comprehensive.
In the short time since full probe production began in September 2008, the MLP has become a go-to public resource in the burgeoning field of chemical probe production. With at least two more years of guaranteed funding, the number of new targets identified—and the probes to accompany them—will only rise in the hopes of quickening highly targeted drug discovery.
source: cell.com
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Increasing The Odds Of Hit Iidentification By Screening Against Receptor Homologs
Last Updated on Saturday, 24 July 2010 04:24 Written by Editor Monday, 12 July 2010 10:31
Abstract— Increasing the odds of hit identification in screening
is of significance for drug discovery. The odds for finding a hit
are closely related either to the diversity of libraries or to the
availability of focused libraries. There are no truly diverse
libraries and it is difficult to design focused libraries without
sufficient information. Hence it is helpful to consider alternative
approaches that can enhance the odds using existing libraries.
Multiple members of a protein family have been considered
collectively in inhibitor design, on the basis of the correlation
between protein families and ligands derived from specific
compound classes. Such a correlation has been exploited in
various drug discovery studies and a general receptor-homologbased
screening scheme may be devised. The feasibility of such a
scheme in enhancing the odds of hit identification is discussed.
Index Terms—Homolgy, inhibitors, screening.
I. INTRODUCTION
High-throughput screening and virtual screening has
been extensively used in drug discovery [1, 2]. The odds
for finding a hit depends on the diversity of compound
libraries used [3]. There is no truly universal set of
representative compounds and the screening has practically
been conducted against subsets of molecules [4, 5x], which
may result in useful hits being missed. This problem was
illustrated recently by Oldenburg [3] in an example of two
highly similar compounds of the steroid family, testosterone
and estrogen, which differ only by a methyl group and a few
double bonds. If only the first is included in a library for
screening against estrogen receptor, estrogen would not be
discovered. The same is true if one starts with estrogen and
tests it against testosterone receptor.
Such a problem is likely of particular concern to
screening for agonist/activator drugs that generally require
more specific structural binding configuration than that of
antagonist/inhibitor drugs. A search of Medline shows that
less than 12% of the publications in drug screening are related
to agonist/activator drugs, which may be partly due to the
difficulty in finding an agonist or activator hit.
Agonist/activator drugs constitute an important drug class. A
search of the therapeutic target database [5] finds 44 targets of
agonist/activator drugs, many of which are important
receptors. Hence, methods for improving the odds of
screening of agonist/activator drugs as well as
antagonist/inhibitor drugs are potentially useful in new drug
discovery.
Increasing the size of libraries in a random fashion may not
always be effective or practical for solving this problem [4].
Drug-like compounds have been found sparsely distributed
through chemistry space [6]. As a result, the design of focused
libraries can be a difficult task without sufficient information.
Therefore it is helpful to consider alternative approaches that
can potentially enhance the odds of hit identification without
relying solely on the simple expansion of existing libraries.
Recent developments in exploiting the correlation between
protein families and ligands from specific compound classes
point to a receptor-homolog-based screening scheme for
improving the odds of hit identification.
II. EXPLOITATION OF THE CORRELATION BETWEEN
PROTEIN FAMILIES AND LIGANDS DERIVED FROM
SPECIFIC COMPUND CLASSES
In the search of inhibitors of specific cyclin-dependent
kinases, multiple members of the kinase family were
considered in a collective manner on the basis of their
common feature of ligand-binding mode [7]. Based on the
known binding mode of purine olomoucine at the ATPbinding
site, compounds were designed from combinatorial
libraries of 2,6,9-trisubstituted purines. Selective inhibitors for
subsets of cyclin-dependent kinases were developed from
these libraries.
The correlation between members of kinase family and
inhibitors derived from specific compound classes has been
shown and exploited in various studies [8]. For instance,
compounds based on quinazoline scaffold were found to
exhibit good structure-activity relationship against EGFR
tyrosine kinase and other related kinases (30-34). Potent ATPbinding
site inhibitors were derived from this scaffold for
EGFR tyrosine kinase (31 or 32), c-erbB2/c-erbB4/EGFR (42,
45, 62), RAF kinase (61), CSF-1R (47, 51), and VEGFR (63-
72), some of which are undergoing clinical trials. Inhibitors
were derived from the phenylamino-pyrimidine class for
PDGFR (80?), PKC-a (75) and EGFR tyrosine kinase (82). A
number of indolocarbazole derivatives were found to be
inhibitors of NGF receptor (210), protein kinase C (215), and
PDGR (213). Pyrazolo[d]pyrimidine derivatives were
designed as inhibitors of LcK (120), v-Src (220), CSF-1R
(47), and EGFR (47).
Increasing The Odds Of Hit Iidentification By
Screening Against Receptor Homologs
Yuzong Chen, Congzhong Cai , Zerong Li , Lianyi Han and Jifeng Wang
H
This correlation also appears in other protein families and
applies to agonists/activators. A few examples are serine
protease and peptide-like inhibitors (x1), nuclear hormone
receptors and steroid agonists (x2), and members of G-protein
coupled receptors and catecholamine agonists (x2).
There have been suggestions of exploiting this relationship
to various drug discovery problems [10]. It was proposed that,
by screening a common and diverse set of small molecule
inhibitors against a set of proteins from a family, specific
structure-activity relationship homology can be derived from
which potential drug discovery targets can be grouped (z1).
Based on the common molecular theme for ligands with a
certain classes of drug targets it was suggested that, in stead of
putting barriers of high-risk targets through expensive screens
of large compound collections, focused libraries of specific
compound classes should be tested first [9]. In order to direct
discovery processes to tractable chemical libraries, potential
targets can be screened from all members of a gene family that
have proven records in drug development and chemistry effort
can then be focused on the most intriguing targets (z2).
A. Screening against of receptor-homologs as a general
scheme?
It is of interest to explore the possibility of further
extending the protein-family-based approach into a more
general receptor-homolog-based scheme for drug screening.
In this scheme, as illustrated in Figure 1, screening is
conducted against a receptor and its homologs which are
defined as proteins of similar sequence in the ligand-binding
domain. These homologs likely share common structural
features at ligand-binding sites and structurally similar ligands
may exist for some of these homologs. If one or more of these
ligands is identified as a hit for the entire homolog group, the
rest may be generated by focused library design based on the
identified hits. The subsequent screening of these focused
libraries against the receptor may lead to the identification of
the specific ligands for that receptor.
In the testosterone-estrogen example, if the same set of
compounds is used for screening against estrogen receptor and
all of its sequence homologs (including testosterone receptor),
testosterone would be identified as a hit for the entire receptor
group. A focused library of steroid analogs may be
constructed based on the framework of testosterone, which
likely include estrogen. A subsequent screening of this
focused library against estrogen receptor would discover
estrogen. The odds of finding an agonist hit are thus
significantly increased.
The feasibility of this scheme depends on the existence of
structurally similar ligands, particularly agonists/activators,
for at least some of the homologs. Structurally similar agonists
are searched for two receptors, estrogen receptor and
adrenoceptor, and their sequence homologs. The identified
homologs of these receptors along with structurally similar
agonists are given in Table 1 and 2 respectively. Certain
homologs are excluded from these two groups which include
orphan receptors with unknown ligand and peptide-agonist
receptors or lipid-agonist receptors with binding sites covering
sections different from that of the respective common binding
sites defined by the estrogen receptor or adrenoceptor [11,12].
Structurally similar agonists are found for 7 out of 8 homologs
of estrogen receptor [13-15] and for 4 out of 8 homologs of
adrenoceptor [16-19] respectively. Moreover, agonist
superficially similar to the other agonists is found for a
homolog of estrogen receptor and that of adrenoceptor
respectively. Thus it appears that compounds of common
structural framework can be found for a substantial portion of
receptor homologs.
III. CONCLUSION
The correlation between protein families and ligands of
common structural theme has been exploited in various drug
discovery studies. A general receptor-homolog-based
screening scheme may be devised based on this correlation.
From the study of specific cases, it appears to be feasible to
use this scheme to enhance the odds of hit identification.
References
[1] Ohlstein, E. H. et al. (2000) Drug discovery in the next
millennium. Annu. Rev. Pharmacol. Toxicol. 40, 177-191
[2] Schneider, G. and Bohm, H-J. (2002) Virtual screening
and fast automated docking methods. Drug Discov. Today 7,
64-70
[3] Oldenburg, K.R. (2001) Optimizing screening
technology: how much to invest? – Reply. Drug Discov.
Today 6, 128-129
[4] Hann, M. and Green, R. (1999) Chemoinformatics – a
new name for an old problem? Curr. Opin. Chem. Biol. 3,
379-383
[4] Chen, X. et al. (2002) TTD: Therapeutic Target
Database. Nucleic Acids Res.30, 412-415
[5] Lipinski, C.A. (2000) Drug-like properties and the
causes of poor solubility and poor permeability. J. Pharmacol.
Toxicol. Methods. 44, 235-249
[6] Gray, N. S. et al. (1998) Exploiting chemical libraries,
structure, and genomics in the search for kinase inhibitors.
Science 281, 533-537
[7] Garcia_Echeverria, C. et al. (2000) ATP site-directed
competitive and irreversible inhibitors of protein kinases.
Med. Res. Rev. 20, 28-57
[8] Thorpe, D.S. (2000) Forecasting roles of combinatorial
chemistry in the age of genomically derived drug discovery
targets. Comb. Chem. High Throughput Screen. 3, 421-436
[9] Caron, P. R. et al. (2001) Chemogenomic approaches to
drug discovery. Curr. Opin. Chem. Biol. 5, 464-470
[10] Costantino, G. and Pellicciari, R. (1996) Homology
modeling of metabotropic glutamate receptors. Structural
motifs affecting binding modes and pharmacological profile of
mGluR1 agonists and competitive antagonists. J. Med. Chem.
39, 3998-4006
[11] Hawtin, S.R. and Wheatley, M. (2000) Critical role of
a subdomain of the N-terminus of the V1a vasopressin
receptor for binding agonists but not antagonists; Functional
rescue by the oxytocin receptor N-terminus. Biochemistry 39,
13524-13533
[12] Steinmetz, A.C.U. et al. (2001) Binding of ligands and
activation of transcription by nuclear receptors. Annu. Rev.
Biophys. Biomol. Struct. 30, 329-359
[13] Lala ,D.S. et al. (1997)Activation of the orphon
nuclear receptor steroidogenic factor-1 by oxysteroids. Proc.
Natl. Acad. Sci. USA 94, 4895-4900
[14] Weatherman, R.V. et al. (1999) Nuclear-receptor
ligands and ligand-binding domains. Annu. Rev. Biochem. 68,
559-581
[15] Rang, H.P. et al. (1999) Pharmacology (4th edn)
(Hunter, L. ed) Churchill livingstone
[16] Arvidsson, L. E. et al. (1984) 8-Hydroxy-2-
(alkylamino) tetralins and related compounds as central 5-
hydroxytryptamine receptor agonists. J. Med. Chem. 27,45-51
[17] Van der Goot, H. and Timmerman, H. (2000)
Selective ligands as tools to study histamine receptors. J. Med.
Chem. 35, 5-20
18] Gerhardt, C. C. et al. (1997) Molecular cloning and
pharmacological characterization of a molluscan octopamine
receptor.Molecular Pharmacology. 51, 293-300
Source: dspace.mit.edu
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Over 5 million compounds screened
Last Updated on Saturday, 24 July 2010 04:24 Written by Editor Monday, 12 July 2010 09:57
In its search for new molecules against malaria, MMV has so far supported the screening of more than 5 million compounds for their potential activity against the malaria parasite. Three partners of the MMV-supported early discovery projects have gone a step further and released the data pertaining to the active molecules into the public domain. This bold move will enable scientists the world over to access these data ensuring their antimalarial potential be used to the full.
GlaxoSmithKline (GSK), have worked to screen more than 2 million compounds from their in-house library for activity against Plasmodium falciparum – the most prevalent strain of malaria parasite in Africa. The screen resulted in the identification of more than 13,500 compounds with activity against the parasite. The largest group of compounds with a known mode of action to be identified was the kinase inhibitors, which are currently being explored in two other MMV-supported projects: GSK miniportfolio and Monash University’s Kinase Platform.
The Genomics Institute of the Novartis Research Foundation has screened more than 800,000 compounds, from a range of sources, resulting in more than 5,600 molecules active against the parasite. Four of these chemical series have been selected for further development at Novartis Institute of Tropical Diseases (NITD). One series is now undergoing candidate selection for clinical trials, while the other three are in lead optimization.
The team from St Jude Children’s Research Hospital has screened more than 300,000 unique chemical structures also against P. falciparum, yielding over 1,100 potent and selective drug discovery starting points. In collaboration with Rutgers University in New Jersey the team at St Jude is working to take these starting points to the next level.
These projects bring the total number of promising compounds to over 20,000.
Data from GSK and St Jude’s screening work has been published in Nature, while all data, including those of Novartis, can be found online through the European Bioinformatics Institute (EMBL-EBI). Sharing these data will not only expedite the discovery and development of future antimalarials it has also set a precedent for other actors in neglected disease drug discovery to follow the open access model.
source: mmv.org
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Increased R&D Efforts Are Overcoming Obstacles and Showing Potential
Last Updated on Saturday, 24 July 2010 10:26 Written by Editor Monday, 12 July 2010 09:46
Posted under Compound Screening, Drug Development, HT Screening, Press Releases | Comments Off
New Study Shows How Worms Can Help Screen For New Drugs
Last Updated on Wednesday, 7 July 2010 04:22 Written by Editor Wednesday, 7 July 2010 04:22
The humble nematode worm could prove of inestimable in screening new compounds on account of active drugs, chic enquiry published today suggests.
Soil-homestead nematodes have a programmed avoidance response to harmful chemicals, which they detect from one end to the other nerves exposed to their conditions. Scientists led by the Wellcome Sureness Sanger Start possess genetically modified the worm C. elegans to make human proteins called receptors in these nerves: the modified worms detect and steer clear of human signalling molecules and soporific candidates.
The exciting results, reported today, 20 July 2006, in the untaken receptive-access journal BMC Biology, promise a simple assay that can be acquainted with to interview thousands of compounds for vim against human proteins – a foundation of drug event.
“The worm is a great tool to understand biology,†said Dr Michelle Teng of the Wellcome Assurance Sanger Alliance, a lead author on the discharge. “Because we understand it so well – it has a undesigning doubtlessly studied in a tizzy set-up – the role on account of each nerve has been mapped in detail. We also would rather a good truce of the signalling mechanisms in nerves that drive the responses.
“We showed that the biochemical response of the receptors emulated that seen in humans. It is very recently that, in the worm, the effects of that response are to make them toady away from the chemical stimulus. This forthright response could be adapted to to test many unknown medicine candidates.â€
Medicines continually interact with receptors, which are “sensors†at the show up of cells. The crew introduced the somatostatin receptor (Sstr2) and the chemokine receptor 5 (CCR5) in the nerves that touched by to environmental cues. Somatostatin is a hormone that mediates a wide sphere of activities in humans and chemokines play an important situation in the immune system. The CCR5 receptor used is also the gateway that HIV/AIDS virus uses to set cells. Both receptors belong to a receptor family called GPCRs, which pretend to be up to 50% of current opiate targets.
The response was specific. In tests, worms responded by avoiding somatostatin or chemokine placed in their paths alone when the pertinent receptor was made in the appropriate nerves.
“We have shown that we can hijack the cellular machinery of the worm so that the man receptor proteins drive the avoidance response,†explained Dr John McCafferty, Principal Investigator at the Wellcome Trust Sanger Institute and senior author. “We chose two receptors with to a large differing functions in humans. The responses were personal to to the compounds we added and could be inhibited in the same way a effect in humans could be restrained.â€
The worms could also be desensitized by pre-exposure to somatostatin or chemokine: desensitization is an important have a share of normal philanthropist response, because it ensures that our receptors can recover repayment for a fresh volley of stimulus. This is the cardinal over and over again that activation has been programmed in these nerves and the team have shown that the human receptors integrate into the worm signalling machinery.
“Systems exist already to study the response of cells in evaluation-tubes to added compounds,†continued Dr McCafferty. “However, because these are ground-dwelling worms which supply on bacteria, we could evaluate crude samples for the purpose antidepressant candidates. Together, these results make us very optimistic that these models longing be widely apt and that development of a boisterous-throughput system is practical.â€
The span used a instantaneous sorting system to isolate the genetically modified worms. Although, for this swat, worm responses were scored below the microscope, automation could be integrated to achieve a higher rate of testing.
The worm model can also alleviate to define which regions of a novel compound are foremost due to the fact that its biological effect, which can be crucial in compensation producing noticeable drugs. The conspire were able to usefulness the worm assay to identify four superior building blocks within the somatostatin molecule which are known to be necessary in the interest of its make.
“These results show the power of oafish organisms such as the worm to help us not only in our understanding of biology but also in the search for untrained ways to improve healthcare,†said Professor Ronald Plasterk, Professor of Developmental Genetics at the University of Utrecht and Director of the Hubrecht Laboratory, in the Netherlands. “It is a comfortably irony of history that the worm was chosen for biomedical examination by Sydney Brenner forty years ago in Cambridge, sole a not many miles from the Sanger Institute. Then twenty years ago John Sulston started to make a gene map of the animal, and long run read its sequence as the elementary of all animal genomes.
“And infrequently a new generation of researchers again in the Cambridge area uses it to test office-seeker drugs that are immediately relevant to sympathetic vigorousness.â€
Publication details
Teng MS et al. (2006) Face of mammalian GPCRs in C. elegans generates novel behavioural responses to human ligands. BMC Biology 4:22 doi:10.1186/1741-7007-4-22
The publication, which is available able of charge, according to BioMed Central’s into operation-access policy, is at: http://www.biomedcentral.com/1741-7007/4/22.
The BMC Biology website is http://www.biomedcentral.com/bmcbiol.
Participating Centres and websites
Wellcome Confidence in Sanger Institute – C. elegans lab:
http://www.sanger.ac.uk/Teams/Team37
Wellcome Trust Sanger Institute – ATLAS Engagement:
http://www.sanger.ac.uk/Teams/Team86
Erasmus Medical Concentrate – Jansen lab:
http://www2.eur.nl/fgg/ch1/cellbiology/jansen
The Wellcome Trust Sanger Initiate, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the centre for UK sequencing efforts. The Institute is responsible suited for the completion of the sequence of approximately one-third of the human genome as equably as genomes of version organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2006, further funding was awarded by the Wellcome Empower to enable the Institute to build on its on cloud nine-class systematic achievements and turn to account the bounty of genome data now available to answer important questions connected with health and disease. These programmes are built surrounding a Faculty of more than 30 higher- ranking researchers. The Wellcome Sureness Sanger Association is based in Hinxton, Cambridge, UK.
http://www.sanger.ac.uk
The Wellcome Trust is the most diverse biomedical fact-finding generosity in the world, spending adjacent to £450 million every year both in the UK and internationally to support and plug delving that will improve the health of humans and animals. The Credit was established impaired the will of Sir Henry Wellcome, and is funded from a unsociable allowance, which is managed with sustained-length of time stability and crop in rail at.
Wellcome Trust Sanger Institute
Hinxton, Cambs, CB10 1SA, UK
http://www.sanger.ac.uk
source: abundanttanzania.qanka.biz
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« Community Group Loses City Funding More Restaurants on Noe Valley’s 24th Street? » UCSF Lab Uses Brains & Street Smarts to Fight Deadly Parasite
Last Updated on Wednesday, 12 May 2010 02:46 Written by Editor Wednesday, 12 May 2010 02:46
A few years ago a chemist made an offer under the table to Jim McKerrow, a professor at UC San Francisco’s Mission Bay campus. McKerrow accepted and drove down to South San Francisco, backed his car up to a loading dock, filled the trunk, and drove away.
“Suddenly I think, oh wow. What if I get stopped by the highway patrol and they open the trunk and there’s all these vials with white powder,†he said, recalling the incident recently. “Now officer, these are protease inhibitors,†he joked.
Back in the mid-1990s, McKerrow adopted another protease inhibitor, K777, in a similarly altruistic maneuver with Jim Palmer, a chemist then working at the now defunct Khepri Pharmaceuticals.
Today, that compound has become a promising candidate in the fight against an infectious parasite that has been found in the Bay Area blood supply and affects millions of victims in Latin America. The culprit—Trypanosoma cruzi (trip-PAN-o-soma CREW-see) —causes the potentially-fatal Chagas disease.
If K777 is successful, which won’t be known until it goes through lengthy clinical trials, it will be the first drug out of UCSF developed independently from industry. In this case, that research was conducted by McKerrow’s lab and its collaborators at the Sandler Center for Basic Research into Parasitic Diseases, a consortium devoted to drug development for neglected diseases.
The latter are infections that are endemic but primarily affect poor people. With Chagas, it’s 8 to 12 million of them, nearly all having lived in rural Latin America at some point in their lives.
An obsolete Brazilian 10,000 cruzado note reflects the importance of the disease in that country, where it was first discovered.
“Instead of on American money – e pluribus unum – here is the life cycle of the parasite sucking blood from someone’s skin,†McKerrow said, pulling a bill out of his desk drawer and pointing to money, which shows a drawing of a benchuca and the skin of its victim, complete with bite mark and parasite-rich feces.
Spread By A Bloodsucking Vector
The T. cruzi parasite – a single-celled eukaryote – is spread by a bloodsucking subfamily of assassin bug called a benchuca, or kissing bug. It bites near a sleeping victim’s eye or mouth, hence its name.
Every time a benchuca has a blood meal, it also defecates. T. cruzi moves from bug to human host when the victim inadvertently scratches the its poop into the bite wound or a mucus membrane.
The Centers for Disease Control and Prevention believe that almost all infections happen outside of the United States, but the parasite, and the insect that spreads it, live in the Southwest and some parts of California. It can also infect animals.
If untreated, 20 to 30 percent of its victims will develop significant, sometimes fatal heart disease, according to the CDC.
No Financial Incentives to Study Chagas
Because the poor are most affected, Chagas isn’t an interesting investment for pharmaceutical development, but it remains important to researchers and countries like Brazil, Argentina, and Bolivia, which have pockets of very high incidence. It’s that importance that leads some to make calls to fellow chemists like McKerrow.
Labs have no financial incentive to look into alternatives to the available treatment for the parasite — nasty drug regimens developed around WWII that have serious side effects including vomiting, psychiatric effects, and nerve damage. But still, scientists remain interested and aware that the latter might be improved on.
So when lawyers for the closing South San Francisco life sciences company told their scientists to destroy the compounds they had been working on to avoid any legal problems, the chemist thought it worth the risk to call McKerrow.
Some of these otherwise doomed compounds, he or she suspected, might be useful to the Sandler Center in fighting parasitic diseases like Chagas and malaria. McKerrow declined to name the chemist.
“It would be a terrible shame to waste stuff in which millions of dollars had been poured into,†Jim Palmer said generally about drugs developed in industry that might get thrown away.
Years earlier, Palmer made a batch of K777 for McKerrow in his free time, hoping the compound would have potential to help treat parasitic infections.
Palmer now works in Australia and said that everything he did with McKerrow was above board, though there are indications that some higher ups in his company at the time – long since dissolved – were uninformed about the relationship initially. “I don’t know anything about that – I don’t remember,†Palmer said.
Palmer was happy about the compound´s progress. He said he named after he saw the very first Boeing 777 airplane waiting to enter service at Dulles International Airport. “It’s like my child,†he said.
K777 was one of about 20 compounds – initially investigated for applications like cancer and arthritis – that were handed over to McKerrow to match against a chemical produced by the Chagas disease parasite.
McKerrow said that the compound has since been legally secured, safe from anyone being able to take out a patent and charge huge sums for it if it.
Though getting drug company throwaways helps, having promising compounds is merely one of many steps in a long and expensive drug development process.
Sandler Center researcher at a chemical hood.
Researchers screened thousands of compounds along the way. Tests for the disease had to be created, as did an animal model, which were designed through the devoted efforts of scientist couple Patricia Doyle-Engle and Juan Engle, according to McKerrow.
The Sandler Center targeted Chagas in particular because Latin American countries have basic infrastructure, like clinics, to distribute medicines once they are developed.
McKerrow said there won’t be a vaccine, since vaccines function to boost immune function, and in later stages of the disease, the host’s own immune response to T. cruzi helps damage heart tissue. Furthermore, there are wild animals like armadillos that are reservoirs for the disease. It’s impossible to eradicate.
Instead, researchers at the Sandler Center are looking at possible drug treatment – protease inhibitors – that stop the action of a chemical the parasite requires throughout its life cycle.
So far, K777 has been shown to be effective in animal tests. The next step is a clinical trial in humans. McKerrow said that the next hurdle is raising roughly $350,000 to pay for manufacturing the drug for such a study according to FDA standards.
Parasites in the Blood Supply
Meanwhile, on the local level, other researchers are tracking Chagas through blood donations.
Studies conducted by San Francisco-based Blood Systems Research Institute found that one out of every 16,000 donors in the San Francisco area tested positive for the parasite. That’s about double the overall U.S. rate.
The CDC estimates roughly 300,000 immigrants have the parasite in the United States.
“Nobody is legally required to screen for T. cruzi in the U.S.,†said Brian Custer, an associate investigator at the institute. He estimated 75 to 80 percent of blood banks nationwide are screening for it, and probably all California blood banks screen for it.
He said he didn’t know anybody that was doing really good outreach, adding that the institute tried to form outreach partnerships with local organizations and clinics, but it was “very, very unsuccessful.â€
The American Red Cross and the institute are the largest blood research entities in the country and the only blood banks studying the infection. Custer said the Blood Systems Research Institute is in an ongoing study of the parasite in Brazil, because little data exists on how Chagas disease progresses after initial infection.
“We really don’t know how it’s contributing to the overall burden of heart disease in the United States,†Custer said.
Rare cases of transmission have occurred in this country. However, infection is closely associated with substandard housing – the benchuca likes crevices that exist in thatched housing – and the vast majority of infections are linked to time spent in certain rural areas of Latin America.
Areas of Argentina have some of the highest prevalence of infection, yet “the likelihood of someone in Buenos Aires having T. cruzi is about the same as someone in San Francisco having the infection,†Custer cautioned.
It’s a disease, like many, with a long tail and may have felled one of the most famous scientists of all.
Charles Darwin wrote about being bitten by a benchuca and suffered from a mysterious illness his whole life. He died from heart failure, and some believe he may have had Chagas.
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Evotec Extends and Broadens Research Agreement with Cubist Pharmaceuticals
Last Updated on Wednesday, 12 May 2010 02:37 Written by Editor Wednesday, 12 May 2010 02:37
Evotec AG / Evotec Extends and Broadens Research Agreement with Cubist Pharmaceuticals processed and transmitted by Hugin AS. The issuer is solely responsible for the content of this announcement.
- Collaboration expanded to include integrated fragment-based drug discovery activities on additional antibacterial targets – Hamburg, Germany – 25 February 2010: Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX) today announced that it has extended its research agreement with Cubist Pharmaceuticals, Inc. (NASDAQ: CBST) to the end of 2010. Under the contract extension, Evotec will provide additional fragment-based drug discovery expertise using its proprietary platform, EVOlution(TM), which includes fragment screening, structural biology and protein crystallography, to discover and profile novel compounds against additional antibacterial targets selected by Cubist.
Evotec and Cubist have collaborated since July 2009, successfully progressing drug discovery programmes. Over the course of 2010, Evotec will continue and expand its support of Cubist’s discovery activities. A key benefit of Evotec’s fragment-based drug discovery platform is its versatility, combining biochemical and biophysical techniques including nuclear magnetic resonance (NMR), surface plasmon resonance (SPR) and x-ray crystallography, thus allowing the design of target-specific strategies.
Dr Mark Ashton, Executive Vice President, Business Development of Evotec commented: “This is further validation of our expertise and capabilities in fragment-based drug discovery. We enjoy the close and productive relationship we have with Cubist’s scientists and look forward to carry on adding significant value to their portfolio of antibacterial programmes.” No financial details are disclosed.
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About EVOlutionTM EVOlutionTM is Evotec’s fragment-based drug discovery platform which combines biochemical and biophysical techniques including nuclear magnetic resonance (NMR), surface plasmon resonance (SPR) and x-ray crystallography for the screening of low molecular weight compounds and fragments. By the combination of the orthogonal screening technologies, Evotec’s fragment screening platform is capable of screening a more diverse set of biological targets than other fragment screening approaches, as well as being able to screen the fragments in a high-throughput mode. The benefit of this is the ability to identify active fragments for numerous classes of biological targets in a short space of time.
For further information, please see: www.evotec.com/fragment-based drug discovery
About Fragment-based Drug Discovery Fragment-based drug discovery (FBDD) is a new paradigm in drug discovery that utilises very small molecules – fragments of more complex molecules – to generate efficient starting points for drug discovery. This approach thus provides the opportunity to effectively manage the molecular weight and overall complexity of drug candidates, a recognised success factor in drug development.
Contact Evotec AG: Dr Werner Lanthaler, Chief Executive Officer, Phone: +49.(0)40.56081-242, werner.lanthaler@evotec.com
and internationally.
The list of risks above is not exhaustive. Our most recent Annual Report on Form 20-F, filed with the Securities and Exchange Commission, and other documents filed with, or furnished to the Securities and Exchange Commission, contain additional factors that could impact our businesses and financial performance.
We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.
source: tmcnet.com evotec.com
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Genentech and UCSF’s Small Molecule Discovery Center Ink Deal Targeting Neurodegenerative Diseases
Last Updated on Wednesday, 12 May 2010 02:26 Written by Editor Wednesday, 12 May 2010 02:26
The University of California, San Francisco and Genentech are partnering to discover and develop drug candidates for neurodegenerative diseases. The company will support the work of several researchers at the UCSF Small Molecule Discovery Center (SMDC) to progress prior SMDC research and Genentech discoveries.
In addition to receiving financial support for its research function, UCSF has the potential for further funding in excess of $13 million if certain development and commercial milestones are met. UCSF will also earn royalties on sales of any resulting products.
This is the first major collaboration that the SMDC has formed with an industry partner, according to Jim Wells, Ph.D., who founded the center in 2005 and serves as its director. Dr. Wells and the center’s associate directors Adam Renslo, Ph.D., and Michelle Arkin, Ph.D., will lead the project.
“What is transformative about this agreement from the university’s perspective is that it is a true collaboration between UCSF and Genentech scientists with the intent to generate drug candidates,†Dr. Wells comments. “This is different from a standard out-license or simple research collaboration.
“Finding targeted compounds is a major obstacle in the drug discovery process in part because most academic researchers don’t have access to this type of facility,†Dr. Wells adds. “This collaboration shows how a center like the SMDC can help support the path from new biology into therapeutic products to help improve patients’ lives.â€
The center is based on high-throughput screening, medicinal chemistry, and fragment-based screening, including a novel approach called tethering, which Dr. Wells pioneered in his previous role as founder, president, and CSO at Sunesis Pharmaceuticals. SMDC offers all UC biomedical researchers access to high-throughput screening and follow-up medicinal chemistry technologies. The center performs biochemical and cell-based assays using liquid-handling robots and a screening library of more than 180,000 compounds. Over the past four years, the center has grown to 18 biologists and chemists, many reportedly with pharmaceutical experience.
SMDC’s arrangement with Genentech builds on the existing master agreement between the company and UCSF, which allows the two to collaborate in a streamlined manner. “To date we have entered into more than 15 research collaborations with UCSF across several therapeutic areas,†comments Marc Tessier-Lavigne, Ph.D., evp, research and CSO of Genentech.
source: genengnews.com
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Study looks at shifting energy metabolism
Last Updated on Wednesday, 12 May 2010 02:25 Written by Editor Wednesday, 12 May 2010 02:25
U.S. scientists say they are using a novel screening technique to identify new effects of drugs in shifting cellular energy metabolism.Researchers at Massachusetts General Hospital, which led the study, said drugs that target the way cells convert nutrients into energy could offer new approaches to treating a range of conditions, including heart attack and stroke.
The team said it identified several FDA-approved agents, including an over-the-counter anti-nausea drug, that can shift cellular energy metabolism processes in animals.
“Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities — like sprinting versus long-distance running,” said Dr. Vamsi Mootha, the lead investigator. “They are also known to be involved in several disease states. We wanted to identify compounds that can safely induce this shift … and investigate their therapeutic potential in animal models.”
The researchers said their findings, which may lead to new therapeutic strategies to treat several serious health problems, appear in the early online edition of the journal Nature Biotechnology.
source: upi.com
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Home » content Shifting cellular energy metabolism may help treat cardiovascular disease
Last Updated on Wednesday, 12 May 2010 01:49 Written by Editor Wednesday, 12 May 2010 01:49
Drugs that target the way cells convert nutrients into energy could offer new approaches to treating a range of conditions including heart attack and stroke. Using a new way to screen for potential drugs, a team led by Massachusetts General Hospital (MGH) researchers has identified several FDA-approved agents, including an over-the-counter anti-nausea drug, that can shift cellular energy metabolism processes in animals. Their findings, being published online in Nature Biotechnology, may open the door to new therapeutic strategies for several serious health problems.
“Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities — like sprinting versus long-distance running. They are also known to be involved in several disease states,” explains Vamsi Mootha, MD, of the MGH Center for Human Genetic Research, who led the study. “We wanted to identify compounds that can safely induce this shift — those that have previously been discovered are too toxic — and investigate their therapeutic potential in animal models.”
Normally cells convert nutrients into energy by relying on two cellular processes. One involves the uptake of sugars that are broken down in the cytoplasm into a molecule called lactate via a process called glycolysis, which quickly yields a small amount of ATP, the enzyme that provides cellular energy. Alternatively, sugars and proteins can be processed in cellular structures called mitochondria to release greater amounts of ATP through a more efficient process called cellular respiration.
In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumor growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia ? a reduction in blood flow ? actually protect tissue against being damaged if its blood supply is later cut off completely.
To search for compounds that shift cells from respiration to glycolysis, Mootha’s team devised a novel screening strategy. They cultured skin cells in two different nutrient environments ? glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose-cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, identified several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.
Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were most interested in finding drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclizine, an over-the-counter drug used to treat nausea and vertigo ? suggesting that it passes the blood-brain barrier ? with few negative side effects.
To investigate meclizine’s potential to prevent tissue damage in heart attack or stroke, Mootha’s team collaborated with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclizine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also found that meclizine’s ischemia protective effects do not appear to involve its known mechanisms.
While the study results suggest that treatment with drugs like meclizine may someday be useful for reducing the damage associated with heart attack or stroke, Mootha stresses that much additional study is needed. “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works,” he says. He also notes that the drug-screening strategy developed by his team could help to identify previously unsuspected beneficial or detrimental effects of other approved drugs.
Mootha is an associate professor of Systems Biology at Harvard Medical School and an associate member of the Broad Institute of MIT and Harvard. Co-lead authors of the Nature Biotechnology article are Vishal Gohil, PhD, and Sunil Sheth, MD, MGH Center for Human Genetic Research (CHGR). Additional co-authors are Roland Nilsson, PhD, Fabiana Perocchi, PhD and William Chen, MGH-CHGR; Jeong Hyun Lee, PhD, and Cenk Ayata, MD, MGH Pathology; Andrew Wojtovich and Paul Brookes, PhD, University of Rochester Medical Center; and Clary Clish, PhD, Broad Institute. The study was supported by grants from the American Diabetes Association and the Smith Family Foundation.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
source: scienceblog.com
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Eli Lilly and GlaxoSmithKline: A Tale of Two Different Pharmas
Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Wednesday, 12 May 2010 01:10
New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly (LLY) and GlaxoSmithKline (GSK) have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
Lilly has a Phenotypic Drug Discover Initiative, (or PD2), launched in 2009. Lilly solicits compounds from other companies so long as they are in certain therapeutic areas (oncology, diabetes, osteoporosis, and Alzheimer’s Disease). Compound structures are sent to Lilly electronically where they are evaluated using modeling and simulation. If the compound passes the screen, the physical compound is sent to Lilly for further testing. If the compound passes the physical test, the fun begins.
All testing by Lilly is free and IP remains with the originating company or institution. What Lilly gets in return is the first right to exclusively negotiate an agreement. If talks break down, the originator keeps all the data generated by Lilly.
Having had some personal experience through my biotechnology company (IMC Biotechnology), I think this is a very interesting approach. We submitted 9 compounds to Lilly and one of them went through the screening process. The software had some minor glitches but the Lilly representatives were very helpful in addressing those glitches.
I think this is a great way for Lilly to expand its repertoire of compounds beyond those invented by its chemists. Certainly one way of going beyond the NIH (not invented here) syndrome.
GSK has come up with an opposite approach where it is offering its library of compounds to researchers in a certain therapeutic area (under-served tropical diseases). For example, it is offering 13,500 compounds that appear to work in malaria. GSK will let other scientists try to develop malaria drugs — free from royalties or other payments to GSK. They were narrowed down from more than 2 million compounds.
More unusual is its open lab project. GSK plans to give up to 60 outside scientists from around the globe access to what it called the “Open Lab,” at an existing company research lab in Spain. Researchers from universities, foundations, etc will be able to use the facilities to try to develop new medicines for diseases plaguing poor countries.
GSK is to start a foundation to fund research and idea sharing, kicking in $8 million initially. It also plans to work with the Emory Institute for Drug Discovery. I have worked a bit with the Emory Institute of Drug Discovery and know they have an excellent drug development team, but have not learnt anything from them about what their exact role in this project is going to be.
While a small fraction of overall R&D efforts, it nevertheless is a significant departure from business as usual. And while GSK does not expect to get royalties, the halo effect, especially with health care reform in the spotlight, cannot be neglected. One could criticize GSK in pointing out that the company does not have much to lose by sharing data in neglected diseases – and that it is not doing so in the more lucrative markets such as oncology. But I doubt that the millions of patients suffering from malaria and TB will support such criticism. New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly and GlaxoSmithKline have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
So the two companies have differing strategies that actually could be quite synergistic. Maybe it is time to pay the ultimate compliment and copy each other.
source: seekingalpha.com
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Scientists Create New Way to Screen Libraries of 10 Million or More Compounds
Last Updated on Wednesday, 12 May 2010 12:53 Written by Editor Wednesday, 12 May 2010 12:53
The search for new drug compounds is probably worse than looking for a needle in a haystack because scientists are limited in the size of the haystacks they can rummage through — time and money make it virtually impossible to screen or search through super-large libraries of potential compounds. This is a serious problem, because there is enormous interest in identifying synthetic molecules that bind to proteins for applications in drug discovery, biology, and proteomics, and larger libraries should mean higher odds of success.But large libraries come with large problems. Because even compounds with only modest affinity (binding to the target protein receptor with less force than those with high affinity) are usually marked as hits, researchers often end up with several hundred of them and, because of practical constraints involving time and money, no easy way to determine which might be the highest affinity or best compound to serve as a starting point to design a drug. These limitations and others have drastically blunted the use of very large libraries — monster libraries — in binding assays.
Now, in research published in the most recent issue of the journal Chemistry & Biology, Tom Kodadek, a professor at The Scripps Research Institute’s Florida campus, and his colleagues at Scripps Florida and the University of Texas Southwestern Medical Center have devised an innovative new way to solve this longstanding problem.
“Current methods severely limit the size of the libraries you can screen,” said Kodadek. “If you get 20 hits out of a 100,000 compound library, it’s feasible to re-synthesize each of those hits to test which are the most effective. But what if you want to screen 10 million compounds? It takes an impossible amount of time to re-synthesize promising compounds for further study. To find the most potent ligands, our new method stands head and shoulders over what is available to researchers today.”
Ligands are compounds that attach to proteins and alter their expression, potentially affecting a particular biomolecular activity, say, a protein pathway involved in a disease.
The new method displays millions of compounds on the surface of resin-based beads, each type of compound on a different bead. The hits are culled from the beads using a unique magnetic signature and then transferred to a microarray format — glass slides or silicon chips that can hold large numbers of compounds on their surface. The microarray format allows quantitative comparison of binding affinity that can be carried out without the need for tedious re-synthesis of many different compounds.
In the study, the team used mixed peptide/peptoid libraries — peptides make up proteins; peptoids are molecules closely related to, but more stable than peptides, making them more convenient for testing — but the method could be applied to any class of compound, according to Kodadek.
Changing the Paradigm
The Kodadek group’s method combines several different technical advances to enable this convenient and efficient screening.
These days, most active molecules are discovered through screening of two basic types. There are functional screens, in which small molecules are introduced into the wells of microtiter plates — flat plates with multiple wells that can reach as high as 9,600 — and tested individually for their ability to alter the activity of an enzyme. Alternatively, there are binding assays, an approach first developed for bead-displayed peptide libraries, where each bead displays many copies of a single molecule.
“Our new method for screening synthetic libraries and characterizing the resultant hits combines many of the features of bead library screening and microarray-based analysis in a seamless fashion,” Kodadek said. “The new technique uses several million beads, each of which displays a unique ligand — theoretically as many as 64 million compounds. The target protein has an antibody attached to it that is covered with iron oxide particles — magnetic dust. If the peptoid ligand is a legitimate ligand, and attaches to the protein, we can pull it from the mass by using a magnetized centrifuge.”
The selected compounds are then removed from the beads through a unique cleaving process and attached to glass microarray slides. These arrays are mixed with different concentrations of the target protein, allowing the affinity strength of each compound on the array to be determined quickly and efficiently.
“This technology is relevant to custom libraries that are produced on beads,” Kodadek said. “Right now, that probably constitutes five percent of screening going on. My guess, however, is that ratio will change once researchers begin to adopt this new method.”
Adoption of this new technique will take time and something of a paradigm shift, Kodadek notes. The new screening technology monitors binding of the bead-immobilized molecule to the target protein; currently, the most widely used high-throughput screens monitor function of the compound. In addition, not all laboratories currently have the equipment and expertise necessary to make microarrays of small molecules.
“I think our method can revolutionize medicinal chemistry,” said Kodadek, “but this is only the first step.”
source: sciencedaily.com
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