| Literature DB >> 19193052 |
Abstract
Drugs can initiate, inhibit, modulate, or potentiate basal activity in cells to produce physiological effects. The interplay between the fundamental affinity and efficacy of drugs with the functional texture imposed on the receptor by the cell (e.g., variation in basal set points or cytosolic signal proteins) generates behaviors for drugs in different tissues that can cause apparently capricious variation between tissues under various physiological conditions. This poses a problem for pharmacologists studying drugs in test systems to predict effects in therapeutic ones. De-emphasis of tissue-specific drug behaviors by reducing drug effects to chemical terms can, to a large extent, reduce the effects of variances in biological systems (changing basal set points, genetic and biochemical variability, etc.). This Perspective discusses the application of four major pharmacodynamic parameters (affinity, efficacy, orthosteric vs allosteric binding, and rate of dissociation of drug from the biological target) to the quantification of biological activity to furnish chemical structure-activity relationships (SARs). These four parameters can be used to quantify effects in test systems and predict subsequent activity in a therapeutic setting. Because at least three different SARs are involved in the drug discovery process (primary therapeutic activity, pharmacokinetics, and safety), with more possible if target selectivity is required, some simple statistical approaches to multivariate structure-activity studies (i.e., primary activity plus selectivity data) also are considered. In total, these data can provide system-independent data to characterize biological activity of molecules in chemical terms that can greatly reduce biologically induced variability.Keywords: Affinity: A measure of the forces that cause a molecule to bind and stay bound to a receptor, inversely proportional to the equilibrium dissociation constant of the ligand–receptor complex (defined as k2/k1; k2 = rate of dissociation of the molecule fro; Agonist: A molecule possessing efficacy such that the behavior of the receptor toward its host cell is altered upon binding.; Allosteric: Binding of molecules to separate sites on the receptor to induce an interaction between them caused by a change in the protein conformation of the receptor.; Antagonist: A molecule that binds to the receptor to prevent the activation of that receptor by an agonist.; Efficacy: The ability of a molecule to cause the receptor to change its behavior toward its host cell.; Full agonist: An agonist that produces the maximal response that matches the maximal capability of the assay to return response.; Null effects: These yield system-independent measures of agonist activity by comparison of drug potencies at concentrations that produce equal effect. It is assumed that if two agonists are tested in a given tissue, then the tissue factors controlling the; Operational model: A theoretical framework to describe agonism in pharmacological systems based on receptor occupancy and a Michaelis–Menten coupling of the receptor to cellular response producing machinery.; Orthosteric: Binding of molecules to a common site such that they compete for occupancy on the receptor.; Partial agonist: A molecule that produces a maximal response that is below what the assay can return as a system maximal response.; Pharmacodynamics: The study of drug interaction with biological targets, that is, receptors.; Pharmacokinetics: The study of drug movement in the body (absorption, distribution, metabolism, and excretion of drugs in vivo).; Rate of dissociation: Rate of diffusion of the molecule away from the receptor once bound (in s−1). This is a measure of the persistence of the ligand occupancy on the receptor and propensity to wash off the receptor once the concentration in the compar; Stimulus–response coupling: The various biochemical pathways that link the cell surface receptor to cell metabolism to provide an observable response to receptor activation.; pIC50: Logarithm of the molar concentration of antagonist producing fifty percent inhibition of a defined pharmacological process. This can be used to quantify antagonist potency, although it has system-dependence that is not operable for pKB estimates. T; pKB: Logarithm of the equilibrium dissociation constant of an ant antagonist–receptor complex. This parameter quantifies the potency of the antagonist.
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Year: 2009 PMID： 19193052 DOI： 10.1021/cb800299s
Source DB: PubMed Journal: ACS Chem Biol ISSN： 1554-8929 Impact factor: 5.100