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

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1 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

2 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-andforth 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.

3 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

4 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.

5 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

6 fragment - a molecular library compound with a lower molecular weight ( 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

7 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 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

8 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.

9 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

10 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 twocarbon tether, and finally a tertiary amine.

11 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

12 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.

13 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 = m). retroinverso - a specific type of peptide isostere that is used to develop a peptidomimetic drug Rule of Five - see Lipinski's rules

14 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 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

15 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

16 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 enzymesubstrate 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.