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Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH)

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journal contribution
posted on 27.12.2011, 00:00 by Anna L. Bowman, Alexandros Makriyannis
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.