, Volume 22, Issue 1, pp 23-34
Date: 23 Aug 2012

Applications of Binding Kinetics to Drug Discovery

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The therapeutic response of a drug is initiated by binding to a physiological target. The efficacy, tolerability and therapeutic index of the drug will be influenced by how efficiently the binding is coupled to physiology. The influence of coupling efficiency on dose-response relationships is determined by drug binding kinetics and drug-induced conformational changes to the physiological target. Binding kinetics determine the affinity of a drug to its target and can impact the coupling efficiency of the drug by affecting the state of equilibrium. The end result may be greater efficacy (exemplified by the angiotensin II receptor 1 antagonists), longer duration of response (muscarinic receptor antagonists), differentiation of therapeutic indications (NSAIDs and ion channel antagonists) and/or greater tolerability (atypical antipsychotics, N-methyl-D-aspartate [NMDA] receptor antagonists, NSAIDs and selective estrogen receptor modulators).

The role of binding kinetics and mechanism in shaping the therapeutic utility of a drug is not captured in the current definition of a successful drug target. This article proposes that a mechanistic definition of a drug target that includes both the macromolecular protein and binding mechanism will help capture the value of discovering a binding mechanism that effectively translates drug binding to a therapeutically useful response. These examples demonstrate that binding kinetics and mechanisms help shape the clinical outcomes that are important to patients and clinicians, namely efficacy, safety, duration of action and therapeutic differentiation.