Document Detail

Computational Study on the Drug Resistance Mechanism against HCV NS3/4A Protease Inhibitors Vaniprevir and MK-5172 by the Combination Use of Molecular Dynamics Simulation, Residue Interaction Network and Substrate Envelope Analysis.
MedLine Citation:
PMID:  23745769     Owner:  NLM     Status:  Publisher    
Hepatitis C virus (HCV) NS3/4A protease is an important and attractive target for anti-HCV drug development and discovery. Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease. However, the emergence of resistance to these two inhibitors reduced the effectiveness of vaniprevir and MK-5172 against viral replication. Among the drug resistance mutations, three single-site mutations at protease site residues Arg155, Ala156 and Asp168 in NS3/4A protease are especially important due to their resistance to nearly all inhibitors in clinical development. A detailed understanding of drug resistance mechanism to vaniprevir and MK-5172 is therefore very crucial for the design of novel potent agents targeting viral variants. In this work, molecular dynamics (MD) simulation, binding free energy calculation, free energy decomposition, residue interaction network (RIN) and substrate envelope analysis were used to study the detailed drug resistance mechanism of the three mutants R155K, A156T and D168A to vaniprevir and MK-5172. MD simulation was used to investigate the binding mode for these two inhibitors to wild-type and resistant mutants of HCV NS3/4A protease. Binding free energy calculation and free energy decomposition analysis reveal that drug resistance mutations reduced the interactions between the active site residues and substituent in the P2 to P4 linker of vaniprevir and MK-5172. Furthermore, RIN and substrate envelope analysis indicate that the studied mutations of the residues are located outside the substrate (4B5A) binding site and selectively decrease the affinity of inhibitors but not the activity of the enzyme, and consequently help NS3/4A protease escape from the effect of the inhibitors without influencing the affinity of substrate binding. These findings can provide useful information for understanding the drug resistance mechanism against vaniprevir and MK-5172. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.
Weiwei Xue; Yihe Ban; Huanxiang Liu; Xiaojun Yao
Related Documents :
24508129 - Hts followed by nmr based counterscreening. discovery and optimization of pyrimidones a...
23363739 - Inhibitory effects and specificity of synthetic sialyldendrimers toward recombinant hum...
24626389 - Unprecedented catalytic performance in disordered nickel niobate through photo-synergis...
23105119 - Roles of subunit nuok (nd4l) in the energy-transducing mechanism of escherichia coli nd...
23836539 - Discovery of an acyclic nucleoside phosphonate that inhibits mycobacterium tuberculosis...
24116139 - A remote palm domain residue of rb69 dna polymerase is critical for enzyme activity and...
7342589 - A predicted secondary structure of protein protease inhibitors.
3923789 - Interactions of a variety of lipoxygenase inhibitors with a supplementary binding site ...
583399 - Biosynthesis of chloramphenicol in streptomyces species 3022a: the nature of the arylam...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-6-9
Journal Detail:
Title:  Journal of chemical information and modeling     Volume:  -     ISSN:  1549-960X     ISO Abbreviation:  J Chem Inf Model     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-6-10     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:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

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

Previous Document:  Transmission of Streptococcus dysgalactiae subsp. equisimilis between Child and Dog in an Aboriginal...
Next Document:  Disability and health: exploring the disablement experience of young adult African Americans.