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.
Description
Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH) - Journal of Chemical Information and Modeling (ACS Publications)
%0 Journal Article
%1 Bowman2011DynamicPharmacophore
%A Bowman, Anna L.
%A Makriyannis, Alexandros
%D 2011
%J Journal of Chemical Information and Modeling
%K MD drug-design dynamic-pharmacophore pharmacophore
%N 12
%P 3247-3253
%R 10.1021/ci200371z
%T Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH)
%U http://dx.doi.org/10.1021/ci200371z
%V 51
%X 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.
@article{Bowman2011DynamicPharmacophore,
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. },
added-at = {2017-03-09T20:36:36.000+0100},
author = {Bowman, Anna L. and Makriyannis, Alexandros},
biburl = {https://www.bibsonomy.org/bibtex/2b3b79ef434d7f73a373f0f7f7e6444c1/salotz},
description = {Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH) - Journal of Chemical Information and Modeling (ACS Publications)},
doi = {10.1021/ci200371z},
eprint = {http://dx.doi.org/10.1021/ci200371z},
interhash = {5110bcb18f7e9e09f9dbb606ae5a4ec3},
intrahash = {b3b79ef434d7f73a373f0f7f7e6444c1},
journal = {Journal of Chemical Information and Modeling},
keywords = {MD drug-design dynamic-pharmacophore pharmacophore},
note = {PMID: 22098169},
number = 12,
pages = {3247-3253},
timestamp = {2017-03-09T20:36:36.000+0100},
title = {Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH)},
url = {http://dx.doi.org/10.1021/ci200371z},
volume = 51,
year = 2011
}