Biochemical mechanisms of drug action: what does it take for success?

Abstract

Drug discovery is extremely difficult. There are many unanticipated scientific, medical and business challenges to every drug discovery programme. It is important to increase our understanding of the fundamental properties of effective drugs so that we can anticipate potential problems in developing new agents. This article addresses potential drug discovery and development risks associated with the biochemical mechanism of drug action, and proposes simple rules to minimize these risks.

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Figure 1: Equilibrium/steady-state competitive blockade.
Figure 2: Mechanisms of non-equilibrium blockade not in mass-action equilibrium with agonist/substrate.
Figure 3: Compound progression scheme for optimizing non-equilibrium parameters.

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Acknowledgements

The author wishes to thank E. Sjogren and D. Chen for many interesting discussions.

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Competing interests

D.C.S. is employed by Roche Pharmaceuticals.

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DATABASES

Entrez Gene

5α-reductase

Aromatase

COX2

ER

Histamine receptors

Muscarinic receptors

Online Mendelian Inheritance in Man

Chronic obstructive pulmonary disease

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Swinney, D. Biochemical mechanisms of drug action: what does it take for success?. Nat Rev Drug Discov 3, 801–808 (2004). https://doi.org/10.1038/nrd1500

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