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 (α-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 (β-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 IC₅₀ 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

consensus 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 µM

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 CH₂ 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

IC₅₀ - 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 µM.  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 (ΔG^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 (Å) (1 Å = 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 α-helix, β-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

scaffold - a core structure of an active molecule on which different functional groups are substituted.  The scaffold may include general features such as ring systems and tethers connecting ring systems.

scaffold hopping - a technique in lead discovery that involves replacing the scaffold of a promising hit with a different scaffold.  The functional groups on the scaffold are kept the same.

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 (SO₂N) 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 and K_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.