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Approximating protein flexibility through dynamic pharmacophore models: application to fatty acid amide hydrolase (FAAH).

ABSTRACT: A structure-based drug discovery method is described that incorporates target flexibility through the use of an ensemble of protein conformations. The approach was applied to fatty acid amide hydrolase (FAAH), a key deactivating enzyme in the endocannabinoid system. The resultant dynamic pharmacophore models are rapidly able to identify known FAAH inhibitors over drug-like decoys. Different sources of FAAH conformational ensembles were explored, with both snapshots from molecular dynamics simulations and a group of X-ray structures performing well. Results were compared to those from docking and pharmacophore models generated from a single X-ray structure. Increasing conformational sampling consistently improved the pharmacophore models, emphasizing the importance of incorporating target flexibility in structure-based drug design.

SUBMITTER: Bowman AL

PROVIDER: S-EPMC3246545 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Approximating protein flexibility through dynamic pharmacophore models: application to fatty acid amide hydrolase (FAAH).

Bowman Anna L AL Makriyannis Alexandros A

Journal of chemical information and modeling 20111207 12

A structure-based drug discovery method is described that incorporates target flexibility through the use of an ensemble of protein conformations. The approach was applied to fatty acid amide hydrolase (FAAH), a key deactivating enzyme in the endocannabinoid system. The resultant dynamic pharmacophore models are rapidly able to identify known FAAH inhibitors over drug-like decoys. Different sources of FAAH conformational ensembles were explored, with both snapshots from molecular dynamics simula ...[more]

PMID: 22098169

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