Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV‐1 protease by enhanced conformational sampling

2018 ◽  
Vol 86 (12) ◽  
pp. 1294-1305 ◽  
Author(s):  
Jianzhong Chen ◽  
Cheng Peng ◽  
Jinan Wang ◽  
Weiliang Zhu
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanism ◽  
Conformational Sampling ◽  
Allosteric Inhibitor ◽  
Hiv 1

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate†

Biochemistry ◽  
2002 ◽  
Vol 41 (16) ◽  
pp. 5150-5162 ◽  
Author(s):  
Adrian S. Ray ◽  
Zhenjun Yang ◽  
Junxing Shi ◽  
Ann Hobbs ◽  
Raymond F. Schinazi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanism ◽  
Mechanism Of Inhibition ◽  
Hiv 1

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

2021 ◽  
Author(s):  
Masahiko Taguchi ◽  
Ryo Oyama ◽  
Masahiro Kaneso ◽  
Shigehiko Hayashi
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Ligand Binding ◽  
Transition State ◽  
Molecular Mechanism ◽  
Binding Affinity ◽  
Free Energy Calculations ◽  
Drug Resistant ◽  
Transition State Analog ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

scholarly journals Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

2021 ◽  
Author(s):  
Masahiko Taguchi ◽  
Ryo Oyama ◽  
Masahiro Kaneso ◽  
Shigehiko Hayashi
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Ligand Binding ◽  
Transition State ◽  
Molecular Mechanism ◽  
Binding Affinity ◽  
Free Energy Calculations ◽  
Drug Resistant ◽  
Transition State Analog ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

scholarly journals Elucidating a Relationship between Conformational Sampling and Drug Resistance in HIV-1 Protease

Biochemistry ◽  
2013 ◽  
Vol 52 (19) ◽  
pp. 3278-3288 ◽  
Author(s):  
Ian Mitchelle S. de Vera ◽  
Adam N. Smith ◽  
Maria Cristina A. Dancel ◽  
Xi Huang ◽  
Ben M. Dunn ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Conformational Sampling ◽  
Hiv 1

Drug resistance among patients with HIV-1

2013 ◽  
Vol 4 (5) ◽  
pp. 317-323
Author(s):  
Miłosz Parczewski
Keyword(s):  
Drug Resistance ◽  
Hiv 1
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