Work

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

Year: 2011

Type: article

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.

Source: Journal of Chemical Information and Modeling

DOI: 10.1021/ci200371z

Authors: Anna L. Bowman, Alexandros Makriyannis

Institution: Northeastern University

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

Open Access status: green

Funders: National Science Foundation, Office of Science, National Institute on Drug Abuse

Awards: G3722163554, G6115428601