Document Detail


Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling.
MedLine Citation:
PMID:  14703123     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by +/- 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 A RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.
Authors:
Robin J Rosenfeld; David S Goodsell; Rabi A Musah; Garrett M Morris; David B Goodin; Arthur J Olson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  17     ISSN:  0920-654X     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2004-01-01     Completed Date:  2004-07-23     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  525-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Automation
Binding Sites
Computer Simulation*
Crystallography, X-Ray / methods
Drug Design
Imidazoles / chemical synthesis,  chemistry*
Ligands
Models, Molecular
Structure-Activity Relationship
Thiazoles / chemical synthesis,  chemistry*
Grant Support
ID/Acronym/Agency:
GM-17844/GM/NIGMS NIH HHS; GM-41049/GM/NIGMS NIH HHS; P01GM48870/GM/NIGMS NIH HHS; P41RR08605/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Imidazoles; 0/Ligands; 0/Thiazoles

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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