Document Detail


Insights into amprenavir resistance in E35D HIV-1 protease mutation from molecular dynamics and binding free-energy calculations.
MedLine Citation:
PMID:  16794810     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Drug resistance is a very important factor contributing to the failure of current HIV therapies. The ability to understand the resistance mechanism of HIV-protease mutants may be useful in developing more effective and longer lasting treatment regimens. In this paper, we report the first computational study of the clinically relevant E35D mutation of HIV-1 protease in its unbound conformation and complexed with the clinical inhibitor amprenavir and a sample substrate (Thr-Ile-Met-Met-Gln-Arg). Our data, collected from 10 ns molecular-dynamics simulations, show that the E35D mutation results in an increased flexibility of the flaps, thereby affecting the conformational equilibrium between the closed and semi-open conformations of the free protease. The E35D mutation also causes a significant reduction of the calculated binding free energies both for substrate and amprenavir, thus giving a plausible explanation for its ability to increase the level of resistance. One possible explanation for the emergence of this mutation, despite its unfavorable effect on substrate affinity, might be the role of E35D as an escape mutation, which favors escape from the immune system in addition to conferring drug resistance.
Authors:
Heike Meiselbach; Anselm H C Horn; Thomas Harrer; Heinrich Sticht
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-06-23
Journal Detail:
Title:  Journal of molecular modeling     Volume:  13     ISSN:  0948-5023     ISO Abbreviation:  J Mol Model     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-25     Completed Date:  2007-09-24     Revised Date:  2013-03-15    
Medline Journal Info:
Nlm Unique ID:  9806569     Medline TA:  J Mol Model     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  297-304     Citation Subset:  IM    
Affiliation:
Abteilung für Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution / genetics*
Aspartic Acid / genetics
Carbamates / pharmacokinetics*
Drug Resistance, Viral / genetics*
Glutamic Acid / genetics
HIV Protease / genetics*,  physiology
HIV Protease Inhibitors / pharmacokinetics*
HIV-1 / enzymology,  genetics*
Humans
Protein Binding / genetics
Sulfonamides / pharmacokinetics*
Thermodynamics*
Chemical
Reg. No./Substance:
0/Carbamates; 0/HIV Protease Inhibitors; 0/Sulfonamides; 161814-49-9/amprenavir; 56-84-8/Aspartic Acid; 56-86-0/Glutamic Acid; EC 3.4.23.-/HIV Protease

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


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