期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 51, 期 12, 页码 3247-3253出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci200371z
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资金
- National Institutes of Health, National Institute on Drug Abuse [DA027965]
- National Science Foundation Research Coordination Network [0639193]
- National Science Foundation
- U.S. Department of Energy's Office of Science
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0639193] Funding Source: National Science Foundation
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.
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