Glossary

absorption - the movement of a drug from its site of administration

to the bloodstream
active pharmaceutical ingredient (API) - the chemical in an
administered drug that is responsible for its biological activity
adverse effect - an undesired effect of a drug

alkaloid - a molecule found in a natural source with a basic nitrogen
and a level of structural complexity
allosteric site - a site on an enzyme or receptor that is not bound by
a substrate or response-causing ligand. Noncompetitive inhibitors
(enzymes) and noncompetitive antagonists (receptors) bind at
allosteric sites.
alpha-helix (!-helix) - a type of secondary structure in which the
protein backbone assumes a spiral conformation
amide linkage - the amide bond formed between individual amino
acid residues in a protein backbone
analgesic - pain killer
analogues - compounds related to a lead and prepared in an attempt
to optimize the desired properties of the lead
API - see active pharmaceutical ingredient
apparent volume of distribution (V
d
) - a hypothetical volume of
plasma that is required to contain a specified drug dose
area under curve (AUC) - the area beneath a C
p
-time curve. AUC is
a measure of drug exposure.
arsenicals - an early synthetic drug class that was used to treat
syphillis and certainly protozoan infections
assay - a general term for testing the biological activity of a
molecule. An assay may be performed either in vivo or in vitro.
AUC- see area under curve
beta-sheet ("-sheet) - a type of secondary structure in which the
protein backbone assumes a fairly flat shape formed by a back-and-
forth flow of the chain
binding energy - the free energy of binding between a drug and its
target based on the dissociation equilibrium constant between the drug
and target (K)

bioavailability (F) - the fraction of an drug dose that actually
reaches the bloodstream from its site of administration
bioequivalence testing - an abbreviated clinical trial used by generic
manufacturers to show that a generic product is biologically similar to
an existing branded drug
bioisosteres - isosteres that specifically preserve electronic and
hydrogen bonding characteristics when one group is exchanged with
another
bolus - an amount of drug that is administered, typically
intravenously, in a single burst
Caco-2 cells - a cell that is used in cell permeability assays
cell permeability - the ability of a molecule to passively cross cell
membranes. High cell permeability indicates that a molecule will likely
be well absorbed from the digestive system.
central compartment - blood plasma
Cheng-Prussoff equation - an equation that can convert
an IC
50
value to a K
i
value

classical isosteres - isosteres that specifically preserve steric bulk
when one group is exchanged with another
clearance (CL) - the removal of a drug from the bloodstream,
normally by either excretion or metabolism. The variable CL has units
of either mL/min or mL/min/kg.
clinical candidate - see investigational new drug
combinatorial chemistry - a method, often automated, for making
large collections of molecules using varied building blocks around a
molecular scaffold
compartment model - a method for describing how a drug
distributes into the various tissues of an organism
competitive inhibitor - an enzyme inhibitor that binds at the active
site of an enzyme. Competitive inhibitors decrease the affinity of an
enzyme for its substrate, and therefore increases K
m
.
composition of matter - a type of patent that covers new chemical
substances, especially drugs
compound library - a collection of molecules that can be used to test
for biological activity against a protein target
concensus scoring - the use of multiple scoring methods in an in
silico screen to increase the relability of the resulting hits
C
p
- see plasma concentration
CYP - see cytochrome P-450
cytochrome P-450 (CYP) - a superfamily of enzymes, mostly
associated with the liver, that perform many oxidative metabolic
reations on drugs
depolarization - the flow of ions across a cell membrane from the
side with high concentration to the side with low concentration
desensitization - an abnormally low response to a drug, often
because of downregulation of a receptor
directed combinatorial chemistry - the use of combinatorial
chemistry to generate libraries focused upon the SAR around a lead
distribution - the transport of a drug to and from its site of action by
the bloodstream
distribution phase - the time period during which an absorbed drug
reaches its full volume of distribution
docking - the computer simulation of a molecule's binding to a target
protein
downregulation - a decrease in receptor expression by a cell in
response to a continuous, high-level stimulation of the receptor
drug-like - a description of a compound with a molecular weight
between 400 and 500 g/mol and a lipophilicity (log P) of near 5
drug product - the entire administered drug. For orally delivered
drugs, the drug product includes the drug substance and all the
binders, dyes, and fillers in the pill.
drug substance - the active material within a drug product
drug-target residence time - the half-life of a drug-receptor
complex as it equilibrates between its bound and unbound state
elimination - any process that causes a decrease in the concentration
of a drug in the bloodstream. Both metabolism and excretion are
elimination processes.
elimination phase - the period of time after a drug has reached its
full volume of distribution and is being cleared from the plasma
elimination rate constant (k
el
) - a rate constant that describes rate
of elimination for a drug. Elimination rate constants normally
correspond to first-order processes and have units of inverse time.
endogenous ligand - a ligand that is found naturally in the body
enzyme (E) - usually a protein, a biological catalyst that converts a
substrate to a product
enzyme-substrate complex (E-S) - the aggregate substance
formed by binding between an enzyme and its substrate
excretion - the removal of waste from the body. For drugs, excretion
is normally associated with the generation of urine by the kidneys
through the filtration of blood.
exogenous ligand - a ligand that is not naturally found in the
body. Synthetic drugs that bind receptors are exogenous ligands.
extraction ratio - the fraction of a drug that is removed by an organ
based on the plasma concentration of a drug that enters and leaves
the organ
F - see bioavailability
false negatives - compounds that fail to appear active in a screen
despite the fact that the compounds do possess strong binding to the
target of interest
false positives - compounds that indicate activity in a screen but are
actually not active
fast neurotransmitter - a neurotransmitter that acts as a ligand for
a ligand-gated ion channel
first pass effect - the tendency for a significant fraction of an oral
drug to be broken down the liver immediately after absorption from
the digestive tract
fragment - a molecular library compound with a lower molecular
weight (150-250 g/mol), fewer non-hydrogen atoms (10-15), and
weaker target binding (K
i
~ 1 mM). Fragments are connected to form
hits.
fragment-based drug discovery (FBDD) - a method of discovering
hits by linking smaller, weaker binding molecules (fragments) together
to make molecules with hit-like activity
G-protein-coupled receptor (GPCR) - a receptor superfamily that is
a very common drug target and affects many metabolic functions
glucuronic acid - a highly polar molecule that is conjugated with
molecules, normally carboxylic acids, to facilitate excretion by the
kidneys
glutathione - a tripeptide that is added to molecules, often phase I
metabolites, to detoxify the compound
half-life (t
1/2
) - the time required for the concentration of a drug to
decrease by 50%
Henderson-Hasselbalch equation - an equation that determines the
ratio of a conjugate base to its acid based upon the pK
a
of the
functional group at the pH of the environment

hepatic clearance (CL
H
) - the elimination of a drug that is
attributable to the liver
hepatic portal system - a collection of blood vessels that gathers
nutrient-rich blood from the gastrointestinal tract and transports it to
the liver
high-throughput screening (HTS) - a quick, automated method of
in vitro screening for determining the activity of a molecule against a
target
hit - a molecule found through screening with a binding affinity of
around 1 !M
homologous series - a collection of analogues in which each
compound differs by the incremental addition of a carbon, usually
characterized by the lengthening of an alkyl chain
homologue - a specific type of analogue which differs from the lead
compound by a single carbon, generally a CH
2
group
hydrogen bonding - an intermolecular force based upon the
interaction of a hydrogen attached to an oxygen or nitrogen with a
nitrogen or oxygen lone pair
hydrophobic effect - an entropy-driven force that favors the binding
of a hydrophobic drug to a target based upon solvation changes
between the bound and unbound drug
IC
50
- the concentration of an inhibitor required to reduce the rate of
an enzymatic reaction by 50%
in vitro - Latin for "in glass". In drug discovery in vitro refers to tests
that are performed within a test tube or other artificial container.
in vivo - Latin for "in the living". In drug discovery in vivo refers to
the activity of molecule upon a living organism.
IND - see investigational new drug
inhibitor - a molecule that slows the reaction between an enzyme and
a substrate
intellectual property space - figurative room around a molecular
structure that allows the original molecule and related compounds to
be protected through patents because no other patents have been filed
on the compounds
intermolecular force - one of several non-covalent interactions that
help bind a drug to its target
interstitial fluid - the liquid that fills the tiny spaces between cells
intravenous (IV) - a method of administration that involves injection
of a drug directly into the bloodstream by way of a vein
investigational new drug - a classification for a molecule that has
been approved to be tested in humans but has not been yet been
approved to be marketed. An investigational new drug is also known
as a clinical candidate.
ionic bond - an intermolecular force based upon the electrostatic
attraction between two oppositely charged ions
in silico screening - the process of estimating a molecule's biological
activity through a computer simulation. The screen involves docking a
molecule into a target's binding pocket and then scoring the quality of
the molecule-target interaction.
isosteres - functional groups that can be interchanged with one
another with minimal impact upon drug-target binding but significant
impact on pharmacokinetics
IV - see intravenous
k
el
- see elimination rate constant
K
i
- the dissociation equilibrium constant of an enzyme-inhibitor
complex
lead - a molecule found through screening with a binding affinity of
around 1 !M. As the lead is modified and optimized, its binding will
increase to the 1-10 nM level.
lead discovery - a stage in the drug discovery process. Lead
discovery involves the screening of molecules to discovery hits and
then selecting the most promising hits as leads.
lead-like - a description of a compound with a molecular weight
between 250 and 350 g/mol and a lipophilicity (log P) of 3 or less
lead optimization - a stage in the drug discovery process. Lead
optimization improves the pharmacodynamics and pharmacokinetics of
the lead until they are potentially good enough for the lead to act as a
drug.
library - see compound library
ligand - a molecule that binds a receptor
ligand-gated ion channel (LGIC) - a receptor superfamily that
controls ion flow across a cell membrane
ligand efficiency (LE) - a calculated molecular descriptor that
estimates the amount of binding energy (!G
o
bind
) contributed by each
non-hydrogen atom (n) in a molecule. Drugs, hits, and leads typical
have a LE value of "0.30 kcal/mol/non-hydrogen atom or smaller.

ligand lipophilicity efficiency (LLE) - a calculated molecular
descriptor that balances a molecule's target binding against its
lipophilicity. LLE values of 3 or higher for a drug, hit, or lead are ideal.

Lineweaver-Burk equation - a linearized form of the Michaelis-
Menten equation that gives the relationship between 1/V and 1/[S]

Lipinski's rules - a set of molecular properties that are simple to
determine and useful for predicting whether a drug will readily diffuse
across a cell membrane
lipophilicity (P) - the equilibrium constant that measures the ratio of
the concentration of a drug in a mixture of 1-octanol and
water. Lipophilicity is often used in a logarithmic form, log P.
magic bullet - a term created by Paul Ehrlich to describe drugs that
are able to destroy an invading organism without affecting the host
maximum tolerated concentration - the maximum concentration
(or dose) of a drug that gives a therapeutic effect without causing
excessive adverse effects. The maximum tolerated concentration is at
the top of the therapeutic window.
me-too drug - a drug that is very similar in structure and activity to a
molecule that has already been approved and marketed
metabolism - the chemical breakdown of a drug, generally caused by
enzymes in the liver
metabolite - the product of a metabolic reaction upon a drug
Michaelis constant (K
m
) - a measure of the affinity between an
enzyme and substrate. Michaelis constants carry a concentration
unit. The Michaelis constant is used in the Michaelis-Menten equation
as well as other enzyme kinetics relationships.
Michaelis-Menten equation - an equation that models the
relationship between the rate of an enzymatic reaction (V) and the
concentration of the substrate ([S])

minimum effective concentration - the minimum concentration (or
dose) require to observe a therapeutic effect of a drug. The minumum
effective concentration defines the bottom of the therapeutic window
of a drug.
molecular library - see compound library
molecular space - a hypothetical collection of molecules that fall
within a defined set of properties or characteristics.
morphine rule - a set a structural requirements that is followed by
most opiates and opioids. The morphine rule requires a molecule to
contain a benzene connected to a quaternary carbon, then a two-
carbon tether, and finally a tertiary amine.
mutational resistance - the ability of a genetically altered organism
to withstand a previously effective drug. Mutational resistance is
frequently encounted in bacteria, viruses, and cancer.
NDA - see new drug application
new drug application (NDA) - a regulatory step in which the FDA
reviews clinical data to determine whether a molecule is safe and
effective enough to be approved as a drug
non-classical isosteres - see bioisosteres
noncompetitive inhibitor - an enzyme inhibitor that binds both an
enzyme and enzyme-substrate complex. A noncompetitive inhibitor
decreases V
max
without affecting K
m
.
nuclear receptor - a receptor superfamily that regulates DNA
replication and gene expression. Steroids generally target nuclear
receptors.
occupancy theory - a theory in ligand-response relationships that
equates the fraction of receptors bound by a ligand to the fraction of
response generated by the receptor
off-label use - the use of a drug in a fashion for which the drug has
not been formally tested or approved
oligopeptide - a short string of amino acids with a length too short to
be called a proper protein. Oligopeptides are normally no longer than
20 amino acids in length. Many signal peptides in the body are
oligopeptides.
one-compartment model - a simple compartment model in which
the drug is assumed to be distributed into only the plasma
oral bioavailability - the fraction of an oral drug that reaches the
bloodstream relative to an IV bolus form of the drug
pan assay interference compounds (PAINS) - molecules that,
because of either a high degree of chemical reactivity or solubility
problems, show up as false positives in screens for activity against a
broad range of protein targets
patent - a form of intellectual property that grants to the holder
exclusive rights to an invention for 20 years from the date of filing
peptidomimetics - a form a lead optimization that attempts to
develop a drug with good bioavailability from a typically poorly
available peptide lead
peptoid - a specific type of peptide isostere that is used to develop a
peptidomimetic drug
pharmacodynamics - the branch of medicinal chemistry that focuses
the action of a drug at its site of action
pharmacokinetics - the branch of medicinal chemistry that focuses
on the movement of a drug from its site of administration, throughout
the body, to its site of action, and out of the body
pharmacophore - the core parts of a molecule that are required for a
threshold level of activity
phase I metabolism - oxidative, reductive, and hydrolytic chemical
reactions on a drug
phase II metabolism - reactions in which a drug or metabolite is
connected to a group (generally very polar) to either detoxify the
compound or assist excretion of the molecule
phenotype - an observable trait of an organism. Symptoms of a
disease are an example of a phenotype, and drugs can modify the
symptoms.
plasma - the non-cellular portion of whole blood. Plasma consists of
water, electrolytes, signal molecules, and proteins.
plasma concentration (C
p
) - the concentration of a drug within the
blood plasma
polymorphism - the ability for most molecules, including drugs, to
pack together in multiple, different arrangements. Each polymorph of
a drug potential has different physical properties and is legally
considered a different composition of matter.
pre-clinical trials - a series of standardized toxicity studies in
animals to establish the safety of a drug and provide data for an IND
application
primary structure - the simplest level of protein structure. Primary
structure describes the order of the amino acids in the peptide
backbone.
privileged structure - a molecular scaffold or part of a scaffold that
appears in molecules that have activity against a range of different
targets
prodrug - a drug that is administered in an inactive form and is
broken down in the body to reveal the active form
product - in the context of enzyme kinetics, the material formed from
the action of an enzyme on a substrate
promiscuous - a description for a compound that binds to multiple
different targets
quaternary structure - the relative orientation of individual proteins
within a multi-protein complex
random coil - a type of secondary structure in which the protein
backbone has no well-defined conformation
receptor - a protein that acts as a switch for controlling cellular
processes
renal clearance (CL
R
) - the elimination of a drug caused by the
kidneys
resolution - a measure of the clarity of an electron density map in X-
ray crystallography. Resolution is measured in angstroms () (1 =
10
-10
m).
retroinverso - a specific type of peptide isostere that is used to
develop a peptidomimetic drug
Rule of Five - see Lipinski's rules
SAR - see structure-activity relationship
screen - a general term for testing the activity of a drug
secondary structure - localized regions of folding within a
protein. Common examples of secondary structure include the "-
helix, #-sheet, and random coil.
sensitization - restoration of a normal response to a ligand, often
because of upregulation of a receptor
serum - the fluid left behind after whole blood is allowed to
clot. Serum is closely related to plasma, but serum lacks some of the
proteins responsible for clotting.
serum albumin - a protein that tends to bind acidic drugs and makes
up between 3 and 5% of the weight of whole blood
scoring - the use of a computer algorithm to estimate the quality of
binding between a molecule and a target protein
selective optimization of side activities (SOSA) - the practice of
discovering new drugs by the modification of old drugs. Normally,
SOSA begins with the screening of a library of varied drugs as a search
for hits.
side effect - see adverse effect
slow neurotransmitter - a neurotransmitter that acts as a ligand for
a G-protein-coupled receptor
spare receptors - extra receptors in a cell or tissue that need not be
bound by a ligand in order to achieve a full response
structural alert - an awareness that a molecule contains functional
groups that frequently lead to drug toxicity. Two common problematic
functional groups are anilines and arylacetic acids.
structure-activity relationship (SAR) - the link between a
compound's molecular structure and its physiological function
substrate (S) - the starting material for an enzymatic
reaction. Substrates bind an enzyme at the enzyme's active site.
sulfa drug - see sulfonamide antibiotics
sulfonamide antibiotics - an early class of antibiotic drugs
containing a sulfonamide (SO
2
N) group
superfamily - the top level of classification for a receptor. The four
superfamilies are ligand-gated ion channels, g-protein-coupled
receptors, tyrosine kinase-linked receptors, and nuclear receptors.
t
1/2
- see half-life
target - typically a protein that plays a key role in a biological
pathway of a disease. Binding of a drug to the protein target often
influences the pathway and affects the diseased condition.
terminal elimination rate constant - the elimination rate constant
than can be observed for a drug that has reached its full volume of
distribution
tertiary structure - the three-dimensional arrangement of secondary
structures within a single protein
therapeutic window - a drug's ideal concentration range, which lies
between minimum effective concentration and maximum tolerated
concentration
total clearance (CL
T
) - the sum of all the drug clearing processes in
the body
trademark - a form of intellectual property that normally applies to
the name brand of a drug. Only a company who owns a trademark
may use the name to market its product.
two-compartment model - a compartment model in which a drug is
presumed to equilibrate between the plasma and a peripheral
compartment
tyrosine kinase-linked receptor (TKLR) - a receptor superfamily
that is commonly targeted to affect cancer
uncompetitive inhibitor - an enzyme inhibitor that binds the
enzyme-substrate complex. An uncompetitive inhibitor decreases
both V
max
andK
m
of an enzyme-substrate system.
upregulation - an increased expression of a receptor in a cell in
response to a lack of stimulation by the receptor
virtual screening - see in silico screening
V
max
- the maximum rate of conversion that a particular enzyme-
substrate system can attain
volume of distribution (V
d
) - see apparent volume of distribution
whole blood - the entire contents of blood including water,
electrolytes, proteins, signaling molecules, and cells
xenobiotic - an unnatural compound in the body. Most drugs are
xenobiotics.