title: 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.
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, USA. a.bowman@neu.edu
authors.forename: Anna L
authors.initials: AL
authors.lastname: Bowman
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases
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