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Applications of Binding Kinetics to Drug Discovery

Translation of Binding Mechanisms to Clinically Differentiated Therapeutic Responses

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Abstract

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.

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Acknowledgements

The author is a full-time employee of Roche Palo Alto. No sources of funding were used to assist in the preparation of this review. The author wishes to thank Dr Michael Bradshaw for critical review of the manuscript and Dr Anthony Ford for insightful discussions.

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  1. Biochemical Pharmacology, Roche Palo Alto LLC, m/s R2-101, 3431 Hillview Ave, Palo Alto, CA, 94304, USA

    David C. Swinney

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Swinney, D.C. Applications of Binding Kinetics to Drug Discovery. Pharm Med 22, 23–34 (2008). https://doi.org/10.1007/BF03256679

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