Data-driven analysis in drug discovery.

In the process of drug discovery for new chemical entities, application of appropriate pharmacological models often is not possible because the molecular mechanism of the compound is not yet elucidated. Therefore, a data-driven approach using generic tools designed to quantify characteristic patterns of concentration-response curves is required. This article outlines the options available for quantifying agonist and antagonist activity. Specifically, for agonists, the use of the Operational model for the determination of functional effects (equimolar potency ratios for full agonists, calculation of relative efficacy) is described. For antagonists, the measurement of pKB (-log of the equilibrium dissociation constant of the antagonist-receptor complex) for orthosteric antagonists that do not alter basal response (simple competitive antagonists), increase basal response (partial agonists), and decrease basal response (in constitutively active systems; inverse agonists) is discussed. In addition, this article considers methods to discern orthosteric receptor antagonism from allosteric antagonism whereby the agonist and antagonist bind to separate sites and interact through a conformational change in the receptor. Methods for the measurement of the pKB for allosteric modulators as well as co-operativity constants for these modulators is described.