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Glossary

Agonist – Any molecule that improves the
activity of a different molecule; e.g., a hormone, which
acts as an agonist when it binds to its receptor, thus
triggering a biochemical response.

Amino acids – A group of 20 different
kinds of small molecules that link together in long chains
to form proteins. Often referred to as the “building
blocks” of proteins. The sequence of amino acids in a
protein determines the structure and function of the
protein.

Analog – A drug whose structure is
related to that of another drug but whose chemical and
biological properties may be quite different.

Antagonist – A molecule that blocks the
ability of a given chemical to bind to its receptor,
preventing a biological response.

Assay – A biological test, measurement
or analysis to determine whether compounds have the desired
effect either in a living organism, outside an organism, or
in an artificial environment.

Bioassay – Determination of the relative
strength of a drug by comparing its effect on a test
organism with that of a standard preparation.

Bioavailability – The percentage of drug
that is detected in the systemic circulation after its
administration. Losses can be attributed to an inherent lack
of absorption/passage into the systemic circulation and/or
to metabolic clearance. Detection of drug can be
accomplished pharmacodynamically (quantification of a
biological response to the drug) or pharmacokinetically
(quantification of actual drug concentration). Oral
bioavailability is associated with orally administered
drugs.

Biotechnology – The industrial
application of living organisms and/or biological techniques
developed through basic research. Biotechnology products
include pharmaceutical compounds and research materials.

Chiral Center

A chiral center is defined as an atom in a molecule that is bonded
to four different chemical species, allowing for optical isomerism.

Combinatorial chemistry (combinational
chemistry or combichem)
– Is used to synthesize large
number of chemical compounds by combining sets of building
blocks. Each newly synthesized compound’s composition is
slightly different from the previous one. A traditional
chemist can synthesize 100-200 compounds per year. A
combinatorial robotic system can produce in a year thousands
or millions compounds which can be tested for potential drug
candidates in a high-throughput screening process.

Combinatorial organic synthesis – A key
feature of combinatorial techniques is that compound
synthesis can be designed such that a range of structures
can be produced simultaneously as mixtures in the same
reaction vessel or individually in parallel using semi-
automated synthesis. The repetitive nature of the synthetic
processes involved in most combinatorial applications lends
itself to automation or semi- automation. This key feature
means that the bench chemist can single- handedly prepare
tens, hundreds, or thousands of compounds of known
structures in the time that it would take to prepare only a
few pure entities by orthodox methodology.

Directed library (focused library)
Library which uses a limited number of building blocks
chosen on the basis of pre-existing information or
hypothesis which defines the type of functionalities deemed
important to obtain a particular activity.

Drug – Any substance presented for
treating, curing or preventing disease in human beings or in
animals. A drug may also be used for making a medical
diagnosis or for restoring, correcting, or modifying
physiological functions.

Drug development process:
•Discovery: Identification of a biological, genetic or
protein target linked to a particular disease; subsequent
lead identification of a potential drug that interacts with
the target to help cure the disease or halt its progression.
•Pre-clinical Phase: Comprehensive in vitro and animal
testing of the drug candidate to establish its target
specificity, toxicity in various doses and pharmacokinetics.
•Clinical Phase I: Human trials conducted to demonstrate
safety and effectiveness (efficacy); tests with paid,
healthy volunteers to establish dosage, side effects and
pharmacokinetics.
•Clinical Phase II: Trials with small numbers of patients
conducted to identify drug performance characteristics
(optimal dosing, administration, key indication).
•Clinical Phase III: Pivotal trials conducted with larger
patient populations to establish efficacy and provide
additional safety information.
•Approval: Data is analyzed and submitted for regulatory
review. The U.S. submission to the FDA is called an NDA (New
Drug Application) or BLA (Biologic License Application); the
European submission to the EMEA (European Medicines
Evaluation Agency) is called an MAA (Marketing Authorization
Application). After stringent analysis and review of the
submission, the regulatory agency provides final approval.

Drug targeting – A strategy aiming at
the delivery of a compound to a particular tissue of the
body.

Enzyme – A macromolecule, usually a
protein, that functions as a (bio) catalyst by increasing
the reaction rate. In general, an enzyme catalyzes only one
reaction type (reaction selectivity) and operates on only
one type of substrate (substrate selectivity). Substrate
molecules are transformed at the same site (regioselectivity)
and only one of a chiral substrate or of a racemate is
transformed (enantioselectivity).

GPCR – G – protein coupled receptors
form a large super – family of proteins composed of three
major classes and more than 30 subfamilies. They are
integral membrane proteins characterized by seven membrane-
spanning (transmembrane; TM) regions. They are involved with
signal transduction across cell membranes. Many medically
and pharmacologically important proteins are included in
this super-family: e.g., Acetylcholine receptors, Dopamine
receptors, and Opioid receptors.

Hard drug – A nonmetabolizable compound,
characterized either by high lipid solubility and
accumulation in adipose tissues and organelles, or by high
water solubility. In the lay press the term refers to a
powerful drug of abuse such as cocaine or heroin.

High – throughput screening (HTS) – Is a
tool in the discovery of pharmaceutical, chemical, and
agricultural compounds. Compounds for HTS are made by either
combinatorial chemistry or by synthetic chemists. During
high-throughput screening (HTS) a large number of compounds
are analyzed, therefore prediction of the pharmacokinetic
properties of drug candidates is an important issue.

Hit – Library component with good level
of desired activity.

Inhibitors – Agents that block or
suppress the activity of enzymes such as proteases.

Ion channel – An integral membrane
protein that provides for the regulated transport of a
specific ions across a membrane.

Isosteres – Molecules or ions of similar
size containing the same number of atoms and valence
electrons.

Lead compound – A compound that exhibits
pharmacological properties which suggest its value as a
starting point for drug development.

Lead discovery – The process of
identifying active new chemical entities, which by
subsequent modification may be transformed into a clinically
useful drug.

Lead generation – The term applied to
strategies developed to identify compounds which possess a
desired but non-optimized biological activity.

Lead optimization – The synthetic
modification of a biologically active compound, to fulfill
stereo electronic, physicochemical, pharmacokinetic and
toxicological clinical usefulness.

Ligand – A small molecule that binds
specifically to a larger one; for example, a hormone is the
ligand for its specific protein receptor.

Ligand design – The design of ligands
using structural information about the target to which they
should bind, often by attempting to maximize the energy of
the interaction.

Lipid – A water-insoluble molecule which
is soluble in nonpolar solvents such as ether. Divided into
two classes: Saponifiable and nonsaponifiable.

Lipophilic – Capable of combining with
or dissolving in lipids.

Lipophilicity – The affinity of a
molecule or a moiety for a lipophilic environment. It is
commonly measured by its distribution behavior in a biphasic
system, either liquid-liquid (e.g., partition coefficient in
1-octanol/water) or solid/liquid (retention on
reversed-phase high performance liquid chromatography
(RP-HPLC) or thin-layer chromatography (TLC) system).

Lipinski’s Rule of 5 – Set of criteria
for predicting the oral bioavailability of a compound on the
basis of simple molecular features ( MolWt <= 500, clogp
<= 5.0, Hbond donors <= 5, Hbond acceptors <=10,
Free-rotation bonds <= 10). Often used to profile a
library or virtual library with respect to the proportion of
drug – like members which it contains. An algorithm,
developed by Christopher A. Lipinski (of Pfizer) and colleagues, in which many of
the cutoff numbers are five or multiples of five. There are
actually four rules, and Pfizer has developed a additional
number of criteria for adoption of lead candidates.

Macromolecule – A molecule having a
molecular weight in the range of a few thousand to many
millions: proteins, nucleic acids and polysaccharides.

Mass spectrometer – A spectroscopic
device in which the masses of particles, ions, and isotopes
are measured. It separates isotopes according to charge and
mass.

Medicinal chemistry – A chemistry-based
discipline, also involving aspects of biological, medical
and pharmaceutical sciences. It is concerned with the
invention, discovery, design, identification and preparation
of biologically active compounds, the study of their
metabolism, the interpretation of their mode of action at
the molecular level and the construction of
structure-activity relationships.

Moieties – Chemical compounds or
functional groups or portions of those compounds.

Molecular modeling – A technique for the
investigation of molecular structures and properties using
computational chemistry and graphical visualization
techniques in order to provide a plausible three-dimensional
representation under a given set of circumstances.

Nanomolar – A concentration representing
one billionth of a mole.

New chemical entity (NCE) – A compound
not previously described in the literature.

Nuclear Magnetic Resonance (NMR) – NMR
spectroscopy makes it possible to discriminate nuclei,
typically protons, in different chemical environments. The
electron distribution gives rise to a chemical shift of the
resonance frequency. The chemical shift of a nucleus is
expressed in parts per million (ppm) by its frequency, n,
relative to a standard, ref, and defined as = 106 (n –
ref)/o, where o is the operating frequency of the
spectrometer. It is an indication of the chemical state of
the group containing the nucleus. More information is
derived from the spin-spin couplings between nuclei, which
give rise to multiplet patterns. Greater detail may be
derived from two- or three- dimensional techniques. These
use pulses of radiation at different nuclear frequencies,
after which the response of the spin system is recorded as a
free- induction decay (FID). Multidimensional techniques,
such as COSY and NOESY, make it possible to deduce the
structure of a relatively complex molecule such as a small
protein (molecular weight up to 25,000).

Optimization – The process of
synthesizing chemical variations, or analogs, of a lead
compound, with the goal of creating those compounds with
improved pharmacological properties.

Parallel synthesis – Strategy whereby
sets of discrete compounds are prepared simultaneously in
arrays of physically separate reaction vessels or micro
compartments without interchange of intermediates during the
assembly process.

Peptide – A molecule composed of two or
more amino acids. Larger peptides are generally referred to
as polypeptides or proteins.

Peptide bond Peptide – A planar, amide
linkage between the amino group of one amino acid and the
carboxyl group of another, with the elimination of a
molecule of water.

Pharmacokinetics – The study of
absorption, distribution, matabolism and excretion (ADME) of
bioactive compounds in a higher organism.

Pharmacology – The science of studying
both the mechanisms and the actions of drugs, usually in
animal models of disease, to evaluate their potential
therapeutic value.

Pharmacophore – A pharmacophore is the
ensemble of steric and electronic features that is necessary
to ensure the optimal supramolecular interactions with a
specific biological target structure and to trigger (or to
block) its biological response. A pharmacophore does not
represent a real molecule or a real association of
functional groups, but a purely abstract concept that
accounts for the common molecular interaction capacities of
a group of compounds towards their target structure.

Potency – Refers to the concentration of
an agent (drug) at which it inhibits an enzyme to a defined
extent, i.e. IC50 is the concentration at which an inhibitor
blocks the activity of an enzyme 50 per cent.

Privileged structure – Substructural
feature which confers desirable (often drug- like)
properties on compounds containing that feature. Often
consists of a semi- rigid scaffold which is able to present
multiple hydrophobic residues without undergoing hydrophobic
collapse.

Prodrug – A chemical structure that
undergoes conversion to an active drug within a biological
system, such conversion usually involving metabolism.

Protease – An enzyme that hydrolyzes
(breaks down a bond and adds water) proteins, especially to
peptides.

Protein – A molecule composed of a long
chain of amino acids. Proteins are the principal
constituents of cellular material and serve as enzymes,
hormones, structural elements, and antibodies. The molar
mass is usually above 100,000.

Protein kinases – Enzymes that
phosphorylate certain amino acid residues (most often Ser,
Thr, or Tyr) in specific proteins.

Quantitative analysis – chemical
determination of the amounts or proportions of constituents
in a substance.

Quantitative Structure – Activity
Relationships (QSAR)
– Mathematical relationships
linking chemical structure and pharmacological activity in a
quantitative manner for a series of compounds. Methods which
can be used in QSAR include various regression and pattern
recognition techniques.

Receptor – A molecule within a cell or
on a cell surface to which a substance (such as a hormone or
a drug) selectively binds, causing a change in the activity
of the cell.

Scaffold – Core portion of a molecule
common to all members of a combinatorial library.

Serine protease – A family of proteases,
characterized by a serine amino acid at its active site.

Solid – phase synthesis – Synthesis of
compounds on a solid surface such as tiny plastic beads. In
solid-phase approaches, pin or bead techniques permit the
synthesis of different molecules on each pin (i.e.,
“one molecule- one bead”). The products of
solid-phase synthesis can be cleaved from the backbone
matrix for solution screening (which is essential when the
screening target is a cell), or the most active molecules
displayed on the polymer surface may be detected using
molecular targets (receptor, enzyme, antibody) pre-tagged
with a means of detection (visible color, fluorescence,
radioactivity, chromophore, etc.) and then isolated and
identified.

Solution phase – Solution-phase
combinatorial approaches have recently become of interest as
an alternative drug discovery avenue for lead discovery and
optimization. The key advantages of solution-phase
combinatorial approaches include an unlimited number of
reactions can be used, therefore, providing maximal
structural diversity, an unlimited reaction scale allows for
the generation of sufficient quantities of libraries to be
derived into different diverse libraries and tested in a
broad range of assays, a large excess of reagents and
solvents, typically required in solid-phase chemistry, are
not needed in solution-phase chemistry, there is no need for
linker manipulation, attachment to and detachment from
resin; therefore, the reaction sequences for library
generation are shorter, soluble intermediates and final
products can be obtained directly for purification and
assays, it is easy to develop and monitor solution-phase
reactions, and it is an efficient way for lead discovery and
optimization from single-compound and complex libraries.

Spectroscopy – Is the analysis of the
lines of light emitted from excited atoms as the electrons
drop back through their orbitals. These lines give the
energy and distances of the electronic orbitals.

Structure – Activity Relationship (SAR)
An analysis which defines the relationship between the
structure of a molecule and its ability to affect a
biological system.

Template – A macromolecular pattern for
the synthesis of another molecule. For example, DNA is a
template for RNA synthesis.

Thematic libraries synthesis – Over the
past several years, combinatorial chemistry has gradually
realigned itself with changing business needs. In many
organizations diversity-driven library production intended
to broadly cover druglike chemical space has to a large
extent been replaced by thematic as well as project-directed
libraries. Thematic libraries are particularly useful for a
platform target-based approach to drug discovery because the
control of a common biochemical theme (e.g., the use of
enzyme inhibitors, peptidomimetics of receptor ligands,
etc.) can often cross over providing leads in several
therapeutic areas.

Three – dimensional Quantitative Structure –
Activity Relationship (3D-QSAR)
– The analysis of the
quantitative relationship between the biological activity of
a set of compounds and their spatial properties using
statistical methods.

Unbiased library – Library prepared from
building blocks chosen without bias towards a particular
target.

Virtual library – A library which exists
solely in electronic form or on paper. The building blocks
required for such a library may not exist, and the chemical
steps for such a library may not have been tested. These
libraries are used in the design and evaluation of possible
libraries.