Bio Screening Industry News

HOUSTON — (December 9, 2009) — On rare occasions, an infant is born with outward appearance of a female but the XY chromosomes of a male. If the child has a normal Y chromosome — the chromosome responsible for testicular development — the condition is known as androgen insensitivity syndrome.

Experts estimate such births occur in about one in 20,000 infants. Other children are born with a partial form of the condition that can affect their genitalia and/or fertility, but how many is not known.

The cause is a wide range of androgen receptor (AR) mutations that fail to perceive the presence of the male hormones testosterone and dihydrotestosterone to differing degrees. How to overcome the problem remained a mystery until Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center experts used a high throughput, automated microscopy technique called high content analysis to solve the puzzle. A report of their findings appears in the current issue of PLoS One, an open access journal.

Reverse effect of mutation

They not only identified the functional abnormality of the AR, but also used high content analysis to “personalize” a treatment that reverses the effects of that mutation.

“With this microscopy technique, we have been able to quantify how the receptor moves and functions inside cells taken from children with normal receptors and in those with the mutation,” said Dr. Marco Marcelli, professor of medicine-endocrinology at BCM and a physician at the Michael E. DeBakey Veterans Affairs Medical Center. He and Dr. Michael Mancini, associate professor of molecular and cellular biology at BCM, and director of its Integrated Microscopy Core, are senior authors of the report.

Androgen insensitivity syndrome

They used banked cells taken from patients – both those with the mutation and those without – to study the action of the receptor in cell cultures grown in the laboratory. Dr. Michael J. McPhaul, a collaborator on the study and a professor of internal medicine—endocrinology at The University of Texas Southwestern School of Medicine Dallas, provided the samples from patients with androgen insensitivity syndrome.

“We did this on a cell-by-cell basis, using high content analysis,” said Mancini. “It is a proof-of-principle study carried out as though we had a patient and a library of hormones. We tried to find the perfect hormone for the mutation through high-speed collection of dozens of measurements from thousands of cells.”

“In two of the three specimens we tested, we found we were able to reverse the activity of the mutated receptor to almost normal,” said Marcelli.

In one patient, large doses of the male hormone dihydrotestosterone were sufficient. In another, they used a synthetic androgen that also activated the receptor.

These approaches overcame the central problem – the mutation changes the shape of the receptor and prevents it from maintaining normal contact with the hormone. It is as though a key is bent and can no longer turn the tumblers in a lock. In these cases, the hormone is designed to go into a pocket created by the receptor. When the pocket is changed by the mutation, the hormone is unable to establish good contact.

“Large amounts of testosterone may create more stable contact,” said Marcelli. “The synthetic androgen may have a conformation that establishes better contact.”

Superandrogen

In the future, scientists may be able to screen large banks of such compounds to find a “superandrogen” that may be even more efficient.

“We might be able to use this technique to create a personalized medicine test,” said Mancini.

Similar techniques might be used to screen drugs for treatment of different cancers, particularly those in which the androgen receptor is responsible for cancer progression. This study proves that the concept is valid providing quantitative information collected quickly on numerous measurements normally requiring separate biochemical tests and huge numbers of cells.

Marcelli said they have yet to use this kind of technique in patients, and such studies will require careful preparation, and go through a variety of approvals before it can be used in clinics. He also said it would be used only in individuals with the partial form of the syndrome. Finding well-matched hormones to defective androgen receptors through screening of thousands of compounds from available libraries could be one of the future developments of this technique.

The paper’s first author, Dr. Adam T. Szafran, an M.D./Ph.D. student who worked in Mancini’s laboratory, championed these studies, said Mancini. Szafran is now finishing the clinical part of his studies at BCM.

Others who took part in this study include Drs. Sean Hartig and Ivan P. Uray, Maria Szwarc, Jennifer Bell, Huiying Sun, Yuqing Shen and Sanjay N. Mediwala, all of BCM. Sun, Shen and Mediwala are also of the MEDVAMC.

Funding for this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the John S. Dunn Foundation and the Veterans Administration.

Source: bcm.edu

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks.

Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” said senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” said co-lead author Jerome S. Pinkner, laboratory manager for Hultgren.

“We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment,” Pinkner added.

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks.

Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease.

When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren said.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he said.

Source: farsnews.com

iThemba Pharmaceuticals’ service division and Pyxis Discovery announced today that they have signed a collaborative agreement to jointly market both companies’ services.
Pyxis’s world class computational chemistry and lead discovery expertise will be coupled with iThemba’s service division to provide medicinal and synthetic chemistry support to projects identified through Pyxis’ international client network. iThemba Pharmaceuticals and Pyxis Discovery also announced today that they are entering into a co-marketing agreement to offer virtual libraries which will be exclusively synthesized for clients. Pyxis’s smart approach of designing and selecting compounds facilitates a rapid and efficient lead discovery and library design process and this coupled to iThemba’s expertise in synthetic and medicinal chemistry will provide our customers with a unique service offering opportunity.
“The intellectual and technological support from Pyxis will enhance both of our service offerings,” said Chris Edlin, CSO of iThemba. “Our customers will gain the advantage of our coupled expertise in design, synthesis and medicinal chemistry prowess.”
“Combining the outstanding medicinal chemistry expertise of iThemba with our design approach helps us to provide our clients with a more complete set of services, resulting in swiftly progressing lead discovery and optimization projects.” said Ron van der Valk, Managing Director of Pyxis Discovery. “In addition to this, we hope that our collaboration with iThemba will support their ambition to bring affordable medicines to the less fortunate people in this world.”
About iThemba Pharmaceutical (Pty) Ltd. (http://www.ithembapharma.com)
iThemba Pharmaceuticals (Pty) Ltd., based in Modderfontein, Gauteng, South Africa is founded to discover and develop new and affordable medicines for the diseases of poverty in Africa. The company is funded by the Biotechnology Regional Innovation Centers, LIFElab and BioPAD of the Department of Science and Technology, Government of South Africa. Utilizing leading edge proprietary technology and its expertise in synthetic organic chemistry, iThemba Pharmaceuticals will become the premier research focal point in Africa for infectious diseases including HIV, tuberculosis, malaria and their associated co-infections. The company will create shareholder value by coupling the company’s own drug discovery efforts with collaborative research initiatives and cash-generating contracts to reduce the risks and costs of developing medicines for neglected diseases and low profit-margin markets.
About Pyxis Discovery B.V. (http://www.pyxis-discovery.com)
The ambition of Pyxis Discovery is to be the preferred chemistry service provider for companies that are active in small molecule drug discovery. Pyxis Discovery’s Smart approach of designing and selecting compound libraries facilitates a rapid and efficient lead discovery process, yielding lead compounds with excellent pharmacological profiles. Pyxis Discovery uses proprietary software algorithms for compound design and selection and a Global Supplier Database of nearly all commercially available screening compounds to provide its clients with screening libraries that are tailored to their specific needs. Furthermore, Pyxis Discovery offers high quality compound libraries off the shelf. Pyxis Discovery is headquartered in the Netherlands and has a worldwide presence with also an office in Boston, Massachusetts and representation in Japan.
Source: Pyxis Discovery B.V.

Source: melodika.net

The Drugs for Neglected Diseases initiative (DNDi) has announced an agreement with drug giant Pfizer that will allow it access to the Pfizer library of novel chemical entities, in order to screen it for compounds that could be developed into new treatments for three of the most neglected infectious diseases of poverty: human African trypanosomiasis (HAT), visceral leishmaniasis (VL) and Chagas disease.

Pfizer vice president Dr Manos Perros said, “We are expanding our commitment to the fight against tropical diseases by joining forces with DNDi by sharing our collection of chemical compounds and the knowledge and expertise associated with these chemical entities”. His colleague Dr Sam Azoulay said, “We are confident that the significant resources and expertise that public-private partnerships such as this one bring together, will accelerate and significantly increase the chances of success in the search for effective new drugs against serious infections that disproportionately affect the poor”.

Under the agreement, scientists in institutes affiliated with DNDi will test at least 150,000 compounds in the Pfizer library against Trypanosoma brucei, Leishmania donovani and Trypanosoma cruzi, the kinetoplastid parasites that cause HAT, VL and Chagas disease, respectively. The researchers will seek compounds that show initial activity against the parasites, and thus might form the basis for novel drug discovery programmes to treat the diseases. The screening will be undertaken at the Eskitis Institute for Cell and Molecular Therapies, Griffith University in Brisbane, Australia (for HAT) and the Institut Pasteur Korea (VL and Chagas disease).

“This agreement provides us access to a compound library of novel chemical entities that has never been explored for kinetoplastid diseases. This marks an important step towards DNDi’s objective of building a robust portfolio and to feed the research and development pipeline with new promising compounds,” said Dr Shing Chang, R&D director at DNDi. In July this year, DNDi announced a similar agreement with Merck – see press release.

Within the same week as the finalising of its agreement with Pfizer, DNDi also announced it is to receive $15 million of Gates Foundation funding over the next five years, which it will use for the development of fexinidazole, currently the only new drug candidate in clinical development for sleeping sickness – see press release. Further information about DNDi is available here.

Source: tropika.net

Contacts: Patty Mattern, University News Service, (612) 624-2801, mattern@umn.edu
John Merritt, Office of the Vice President for Research, (612) 624-2609
Stacie Byars, Celladon, (206) 660-2588

MINNEAPOLIS / ST. PAUL (11/23/2009) —Research conducted by University of Minnesota scientists, in collaboration with Celladon Corporation, has led to the invention of technology to more rapidly identify compounds for the treatment of heart failure.

Chronic heart failure is an increasingly important health problem. It is the leading medical cause of hospitalization and is expected to result in an estimated direct and indirect cost to the health care system of $37.2 billion in 2009 alone. About 5.7 million people in the United States have heart failure, and it contributes to or causes some 290,000 deaths annually. However, developing new treatments is an extremely costly and time-consuming process, taking nearly a decade to gain regulatory approval and requiring hundreds of millions of dollars.

The technology, developed by the universitys David Thomas and Razvan Cornea and Celladon Corporations  Krisztina Zsebo, allows for increased screening efficiency of compounds capable of disrupting the interactions of proteins implicated in the development of heart failure. Fluorescence resonance energy transfer (FRET) is used to measure disruption of the calcium regulatory system, which has long been implicated in cardiovascular disease. This will provide key information on a particular drugs likelihood of success early in the screening process, since compounds that decrease FRET are good candidates for further development.

“Dr. Cornea and I, along with our students, have worked for more than a decade developing methods for preparing membranes from purified components, and using FRET to detect changes in protein interactions,” Thomas said. “Scientists from Celladon saw the potential for drug discovery, and this resulted in a breakthrough that has added an exciting new dimension to our research program.”

The high-throughput assay, developed by the university team, is based on a reconstituted membrane system composed of purified lipid and protein components. This technique is especially important because the interactions of integral membrane proteins are more complex than soluble proteins, making it very difficult to produce a synthetic system that recapitulates the cellular interactions in a large-scale and reproducible manner.

Celladon, based in La Jolla, Calif., has acquired an exclusive license for the technology from the University of Minnesota for the development of molecular therapies for cardiovascular diseases. Celladon also provided funding for the research that allowed Thomas to further refine the assay.

“This technology is very important to the efficient selection and advancement of compounds with the potential to increase cardiac contractility and potentially accelerates product opportunities that will ultimately benefit patients and development partners alike,” said Krisztina M. Zsebo, Ph.D., president and chief executive officer of Celladon Corporation. “Celladon’s investigation and development of first-in-class CDN small molecules as intravenous and oral drugs for the treatment of acute and chronic heart failure sets us apart in the cardiovascular field and presents multiple partnering opportunities.”

Source: umn.edu

Chemical libraries have long been a mainstay in the search for new pharmaceutical compounds, and they have been created using many different paradigms. Vast diverse collections of unique compounds have been screened at high throughput to find appropriate effects on target proteins. Such large libraries continue to be used for drug discovery, but screening smaller, more focused libraries, can provide more efficient solutions with better overall hit rates.

Ten years ago, BioFocus®, a Galapagos company, launched a nonexclusive compound library specifically designed to target serine-threonine and tyrosine kinases. This library, SoftFocus® Kinase library one (SFK01), was designed to mimic the binding of ATP to the catalytic (hinge) region and had a rather simplistic design based around an aminopyrimidine core (Figure 1).

Targeting Kinases

In Silico Design

Current in silico design processes enable automated docking and scoring of scaffold ideas into a variety of known x-ray structures that have been selected, not only for broad coverage of the kinome, but also different conformational states of individual kinase enzymes. The design premise is that, if the core of the molecule or scaffold contains the key recognition groups for binding into one of the known conformational states, it has the potential to target any kinase.

However, as different side chains or monomers are added, the potential to gain specificity for one target over another becomes reality. The various docking methods used in the design of the BioFocus libraries include hinge binding, the DFG-out model, and novel binding modes.

Hinge Binding

DFG-Out Model

An approach to the design of kinase libraries with higher selectivity potential is to target the DFG-out allosteric pocket adjacent to the ATP site. BioFocus has developed a generalized binding model of the DFG-out pocket that enables the targeting of a range of inactive kinase conformations.

Binding Modes

Focusing on Success

By constantly refining the compounds using in silico methods, including those described above and with the development of innovative in silico models and applications such as Cresset BioMolecular’s molecular Field technology, the latest advances in kinase research can be incorporated into novel libraries. Consequently, this may also provide a strong intellectual property position to those who screen them. Indeed, based on the screening of SoftFocus kinase libraries alone, over 70 known patents have been applied for or granted.

A recent example from Galapagos highlights this. Following a screen of some 16,000 BioFocus focused kinase compounds, three hit series were identified that showed structure-activity relationships against a novel rheumatoid arthritis target. Two of these compound series were progressed to the hit-to-lead phase and subsequently one series was optimized, and a compound is currently undergoing clinical trials. The project time from screening to preclinical candidate nomination was three years.

There is no doubt that the drug discovery process should be shortened whenever possible. It is essential to improve the lead discovery process. Focused compound libraries such as the SoftFocus collection have the inherent capabilities to provide a robust hit discovery process, with good hit-to-lead conversion rates and shorter development times.

Furthermore, such libraries can maximize the benefit of new techniques such as in silico modeling, enabling them to be consistently developed over time. BioFocus has also maintained flexibility in its library-generation processes using these techniques, which has enabled the development of novel libraries with proven results.

Source: genengnews.com

Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based in silico screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target.

Both in silico screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats.

Results: Here, we describe the new open source program DG-AMMOS which allows the generation of the 3D conformation of small molecules using Distance Geometry and their optimization via Automated Molecular Mechanics Optimization. The program is validated on the Astex dataset, the ChemBridge Diversity database and on a number of small molecules with known crystal structures extracted from the Cambridge Structural Database.

A comparison with the free program Balloon and the well-known commercial program Omega generating the 3D of small molecules is carried out. The results show that the new free program DG-AMMOS is a very efficient 3D structure generator engine.

Conclusions: DG-AMMOS provides fast, automated and reliable access to the generation of 3D conformation of small molecules and facilitates the preparation of a compound collection prior to high-throughput virtual screening computations.

The validation of DG-AMMOS on several different datasets proves that generated structures are generally of equal quality or sometimes better than structures obtained by other tested methods.

Author: David LagorceTania PenchevaBruno VilloutreixMaria Miteva
Credits/Source: BMC Chemical Biology 2009, 9:6

When we screen zillions of compounds from our files against a new drug target, what can we expect? How many hits will we get, and what percentage of those are actually worth looking at in more detail?

These are long-running questions, but over the last twenty years some lessons have been learned. A new paper in J. Med. Chem. emphasizes one of the biggest ones: if at all possible, run your assays with some sort of detergent in them.

Why would you do a thing like that? Compound aggregation. The last few years have seen a rapidly growing appreciation of this problem. Many small molecules will, under some conditions, clump together in solution and make a new species that has little or nothing to do with their individual members. These new aggregates can bind to protein surfaces, mess up fluorescent readouts, cause the target protein to stick to their surfaces instead, and cause all kinds of trouble. Adding detergent to the assay system cuts this down a great deal, and any compound that’s a hit without detergent but loses activity with it should be viewed with strong suspicion.

The authors of this paper (from the NIH’s Chemical Genomics Center and Brian Shoichet’s lab at UCSF) were screening against the cysteine protease cruzain, a target for Chagas disease. They ran their whole library of compounds through under both detergent-free and detergent conditions and compared the results. In an earlier screening effort of this sort against beta-lactamase, nearly 95% of the hits (many of them rather weak) turned out to be aggregator compounds. This campaign showed similar numbers.

There were 15 times as many apparent hits in the detergent-free assay, for one thing. Some of these were apparently activating the enzyme, which is always a bit of an odd thing to explain, since inhibiting enzyme activity is a lot more likely. These activators almost completely disappeared under the detergent conditions, though. And even looking just at the inhibitors, 90% of the hit set in the detergent-free assay went away when detergent was added. (I should note that control cruzain inhibitors performed fine under both sets of assays, so it’s not like the detergent itself was messing with the enzyme to any significant degree).

They point out another benefit to the detergent assay - it seems to improve the data by keeping the enzyme from sticking to the walls of the plastic tubes. That’s a real problem which can kick your data around all over the place - I’ve encountered it myself, and heard a few horror stories over the years. But it’s not something that’s well appreciated outside of the people who set up assays for a living (and not always even among some of them).

So, let’s get rid of those nasty aggegators, right? Not so fast. It turns out that some of the compounds that showed this problem during the earlier beta-lactamase work didn’t cause a problem here, and vice versa. Even using different assays designed to detect aggregation alone gave varying results among sets of compounds. It appears that aggregation is quite sensitive to the specific assay conditions you’re using, so trying to assemble a blacklist of aggregators is probably not going to work. You have to check things every time.

One other interesting point from this paper (and the previous one): curators of large screening collections spend a lot of time weeding out reactive compounds. They don’t want things that will come in and react nonspecifically with labile groups on the target proteins, and that seems like a reasonable thing to do. But in these screens, the compounds with “hot” functional groups didn’t have a particularly high hit rate. You’d expect a cysteine protease to be especially sensitive to this sort of thing, with that reactive thiol right in the active site, but not so. This ties in with the work from Benjamin Cravatt’s group at Scripps, suggesting that even fairly reactive groups have a lot of constraints on them - they have to line up just right to form a covalent bond, and that just doesn’t happen that often.

So perhaps we’ve all been worrying too much about reactive compounds, and not enough about the innocent-looking ones that clump up while we’re not looking. Detergent is your friend!

Source: corante.com

This publication, showing data from the testing of Quinazoline derivatives in a Spinal Muscular Atrophy mouse model, has been published in Human Molecular Genetics by lead author Dr. Matthew Butchbach from the laboratory of Dr. Arthur Burghes at the Ohio State University.

The generation of the Quinazoline compounds as a therapeutic drug candidate for Spinal Muscular Atrophy was fully funded by Families of SMA.

The paper explores whether the Quinazoline compounds, which increase the expression of SMN2, are useful as potential therapeutics for SMA. Ultrahigh-throughput screening identified substituted Quinazolines as potent SMN2 inducers.  The drug-like properties of the initial screening hits were optimized through directed medicinal chemistry.  This resulted in series of C5-Quinazoline derivatives.

Oral administration of three of these compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system.  The authors then examined the effect of these compounds on the progression of disease in SMNDelta7 SMA mice.  Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss.  Overall the authors summarize that the quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11, and ameliorates the motor phenotype of SMNDelta7 SMA mice.

“This is the first compound series to go from hit-to-preclinical candidate that shows favorable pharmacology in the nervous system and shows benefit to severe SMA mice.  This study shows that promising therapies for SMA can be developed”, said Matthew Butchbach, Ph.D., who is lead author on this publication.

“Families of SMA is pleased that the first test of this class of compounds in SMA mice shows potential therapeutic benefit.  The clinical lead in this series called Quinazoline495, which is a more optimized compound than those tested here, has also been assessed in this animal model with similar results, as well as tested in a slightly less severe mouse model of SMA, in which it showed marked enhancement of survival”, says Jill Jarecki, Ph.D., FSMA research director.

The lead compound Quinazoline495 recently received orphan drug designation from the FDA for the treatment of spinal muscular atrophy.  Please click here to read more.

Families of SMA recently licensed this series of compounds to Repligen Corporation for development as a drug treatment for Spinal Muscular Atrophy.

The full reference:

European chemists have discovered that both mirror-image forms of a particular compound can bind at the same time in the same site of an enzyme, a phenomenon that has never been seen before. The finding has significance for drug discovery screening and studies of how small molecules interact with proteins.

Rolf Breinbauer from Graz University of Technology, Austria, and Wulf Blankenfeldt from the Max Planck Institute of Molecular Physiology in Dortmund, Germany, were studying a metabolic enzyme from a species of the bacterium Burkholderia cepacia, using racemic mixtures of chiral probe molecules to find ones that bound in the enzyme’s active site. In most cases only one form of a chiral (or ‘handed’) molecule would bind at once, but they found that in one instance both enantiomeric forms occupied the binding site at the same time.

‘If you read the textbooks about enantiomers,’ says Breinbauer, ‘there’s a simplified notion that one enantiomer is good and the other is either bad or just idle.’ He explains that for most proteins (apart from certain enzymes that have evolved to cope with wide ranges of substrate molecules) either only one enantiomer will bind, or both can bind individually - with the assumption that one form will be significantly more active than the other. ‘Our findings show that the world is more complicated,’ he adds.

While each individual enantiomer can bind to the enzyme seperately, Breinbauer notes that the arrangement of the molecules within the binding site is quite different when both bind together. This could lead to cooperative effects, producing either an enhanced or diminished response relative to the individual enantiomers.

He adds that this could have relevance in drug discovery screening, where mixtures of both enantiomers of chiral compounds are routinely screened together to find initial hits. ‘People need to consider more options when interpreting binding data from racemic mixtures.’

Dafydd Owen of Pfizer Research Chemistry in  Sandwich, UK, agrees that the finding is an important reminder that chemists need to be open-minded about interpreting screening data. It also highlights the inherent trade-offs made when screening mixtures - particularly in high-throughput screens when mixtures of several compounds are tested at once.

Owen sees most interest in the discovery in the area of fragment-based drug discovery, where small ‘fragment’ molecules found to bind to a drug target are linked together to make potential drug molecules. ‘As a medicinal chemist,’ he adds, ‘my immediate thought was to join the two structures together to incorporate the best of each and make a hybrid.’ He points out, however, that from a fragment point of view it is almost irrelevant to the enzyme that the two molecules happen to be mirror images of each other, ‘despite their apparent similarity, nature views enantiomers as very different molecules’.

Phillip Broadwith

Source: rsc.org