Document Detail

Cyclophilin A inhibition: Targeting transition-state-bound enzyme conformations for structure based drug design.
MedLine Citation:
PMID:  23312027     Owner:  NLM     Status:  Publisher    
Human Cyclophilin A (CypA) catalyzes cis-trans isomerization of the prolyl peptide ω-bond in proteins and is involved in many sub-cellular processes. CypA has, therefore, been identified as a potential drug target in many diseases, and the development of potent inhibitors with high selectivity is a key objective. In computer-aided drug design, selectivity is improved by taking into account the inherent flexibility of the receptor. However, the relevant receptor conformations to focus on in order to develop highly selective inhibitors are not always obvious from available x-ray crystal structures or ensemble of conformations generated using molecular dynamics simulations. Here, we show that the conformation of the active site of CypA varies as the substrate configuration changes during catalytic turnover. We have analyzed the principal modes of the active site dynamics of CypA from molecular dynamics simulations to show that similar ensembles of enzyme conformations recognize diverse inhibitors and bind the different configurations of the peptide substrate. Small non-peptidomimetic inhibitors with varying activity are recognized by enzyme ensembles that are similar to those that tightly bind the transition state and cis configurations of the substrate. Our results suggest that enzyme-substrate ensembles are more relevant in structure-based drug design for CypA than free enzyme. Of the vast conformational space of the free enzyme, the enzyme conformations of the tightly bound enzyme-substrate complexes are the most important for catalysis. Therefore, functionalizing lead compounds to optimize their interactions with the enzyme's conformational ensemble bound to the substrate in the cis or the transition state could lead to more potent inhibitors.
Mulpuri Nagaraju; Lauren C McGowan; Donald Hamelberg
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-13
Journal Detail:
Title:  Journal of chemical information and modeling     Volume:  -     ISSN:  1549-960X     ISO Abbreviation:  J Chem Inf Model     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101230060     Medline TA:  J Chem Inf Model     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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