Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations

The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to exp...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2010, Vol.45 (1), p.227-235
Main Authors: Hu, Guo-Dong, Zhu, Tong, Zhang, Shao-Long, Wang, Dunyou, Zhang, Qing-Gang
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Drug resistance
Drug Resistance, Viral
Enzyme Stability
HIV Protease - chemistry
HIV Protease - genetics
HIV Protease - metabolism
HIV Protease Inhibitors - metabolism
HIV Protease Inhibitors - pharmacology
HIV-1 - enzymology
HIV-1 protease
Medical sciences
MM-PBSA
Molecular Dynamics Simulation
Mutant Proteins - antagonists & inhibitors
Mutant Proteins - chemistry
Mutant Proteins - genetics
Mutant Proteins - metabolism
Mutation
Pharmacology. Drug treatments
Protein Binding
Protein Conformation
Structure-Activity Relationship
Sulfonamides - metabolism
Sulfonamides - pharmacology
Thermodynamics
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Summary:The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor–protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT. ▪The drug resistance mechanisms of three mutants to an inhibitor GRL-98065 are explained by using binding free energies and structural analysis. The results agree well with the experimental results.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2009.09.048