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Nat Rev Drug Discov. 2003 Jul;2(7):527-41.

Implications of protein flexibility for drug discovery.

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  • 1AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicester LE11 5RH, UK. simon.teague@astrazeneca.com

Abstract

Proteins are in constant motion between different conformational states with similar energies. This has often been ignored in drug design. However, protein flexibility is fundamental to understanding the ways in which drugs exert biological effects, their binding-site location, binding orientation, binding kinetics, metabolism and transport. Protein flexibility allows increased affinity to be achieved between a drug and its target. This is crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.

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