Document Detail


Inhibition and substrate recognition--a computational approach applied to HIV protease.
MedLine Citation:
PMID:  14713189     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have developed a computational approach in which an inhibitor's strength is determined from its interaction energy with a limited set of amino acid residues of the inhibited protein. We applied this method to HIV protease. The method uses a consensus structure built from X-ray crystallographic data. All inhibitors are docked into the consensus structure. Given that not every ligand-protein interaction causes inhibition, we implemented a genetic algorithm to determine the relevant set of residues. The algorithm optimizes the q2 between the sum of interaction energies and the observed inhibition constants. The best possible predictive model resulting has a q2 of 0.63. External validation by examining the predictivity for compounds not used in derivation of the model leads to a prediction accuracy between 0.9 and 1.5 log10 unit. Out of 198 residues in the whole protein, the best internally predictive model defines a subset of 20 residues and the best externally predictive model one of 9 residues. These residues are distributed over the subsites of the enzyme. This approach provides insight in which interactions are important for inhibiting HIV protease and it allows for quantitative prediction of inhibitor strength.
Authors:
H M Vinkers; M R de Jonge; E D Daeyaert; J Heeres; L M H Koymans; J H van Lenthe; P J Lewi; H Timmerman; P A J Janssen
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  17     ISSN:  0920-654X     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2004-01-09     Completed Date:  2004-07-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  567-81     Citation Subset:  IM    
Affiliation:
Center for Molecular Design, Janssen Pharmaceutica N.V., Antwerpsesteenweg 37, B-2350 Vosselaar, Belgium. mvinkers@prdbe.jnj.com
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry
Crystallography, X-Ray
Drug Design
HIV Protease / chemistry*,  metabolism*
HIV Protease Inhibitors / chemical synthesis,  chemistry*,  pharmacology*
Kinetics
Models, Molecular
Models, Theoretical
Molecular Conformation
Protein Conformation
Reproducibility of Results
Structure-Activity Relationship
Substrate Specificity
Chemical
Reg. No./Substance:
0/Amino Acids; 0/HIV Protease Inhibitors; EC 3.4.23.-/HIV Protease

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


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