Quantifying biological activity in chemical terms: a pharmacology primer to describe drug effect

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.