Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease

2014 ◽  
Vol 92 (5) ◽  
pp. 357-369 ◽  
Author(s):  
Huiqun Wang ◽  
Lingling Geng ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Computational Study ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Free Energy Decomposition

Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecular modeling techniques is an efficient way to interpret the molecular mechanism of drug-resistance. Our work mainly elaborates the molecular mechanism of drug-resistance of Narlaprevir and further provides valuable information for developing novel, safer, and more potent HCV antiviral drugs in the near future.

scholarly journals Binding Affinities of Sanggenon Derivatives as PTP1B Inhibitors; Using Molecular Dynamics and Free Energy Calculations

2021 ◽  
Author(s):  
Safak OZHAN KOCAKAYA
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Tyrosine Phosphatase ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Free Energy Decomposition ◽  
Poisson Boltzmann ◽  
Ptp1b Inhibitors

Abstract Recently, protein tyrosine phosphatase 1B (PTP1B) inhibitors have become the frontier as possible targeting for anti-cancer and antidiabetic drugs. The contemporary observe represents a pc assisted version to investigate the importance of precise residues within the binding web site of PTP1B with numerous Sanggenon derivatives remoted from nature. Molecular dynamics (MD) simulations were performed to estimate the dynamics of the complexes, and absolute binding unfastened energies have been calculated with exclusive additives, and carried out through the usage of the Molecular Mechanics-Poisson-Boltzmann floor region (MM-PB/SA) and Generalized Born surface vicinity (MM-GB/SA) strategies. The effects show that the expected free energies of the complexes are normally constant with the available experimental statistics. MM/GBSA free energy decomposition analysis shows that the residues Asp29, Arg24, Met258, and , Arg254 in the second active site in PTP1B are crucial for the excessive selectivity of the inhibitors.

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

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 HawkDock: a web server to predict and analyze the protein–protein complex based on computational docking and MM/GBSA

2019 ◽  
Vol 47 (W1) ◽  
pp. W322-W330 ◽  
Author(s):  
Gaoqi Weng ◽  
Ercheng Wang ◽  
Zhe Wang ◽  
Hui Liu ◽  
Feng Zhu ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Interactions ◽  
Decomposition Analysis ◽  
Scoring Function ◽  
Web Server ◽  
Energy Decomposition Analysis ◽  
Energy Decomposition ◽  
Computational Docking ◽  
Free Energy Decomposition ◽  
Key Residues

Abstract Protein–protein interactions (PPIs) play an important role in the different functions of cells, but accurate prediction of the three-dimensional structures for PPIs is still a notoriously difficult task. In this study, HawkDock, a free and open accessed web server, was developed to predict and analyze the structures of PPIs. In the HawkDock server, the ATTRACT docking algorithm, the HawkRank scoring function developed in our group and the MM/GBSA free energy decomposition analysis were seamlessly integrated into a multi-functional platform. The structures of PPIs were predicted by combining the ATTRACT docking and the HawkRank re-scoring, and the key residues for PPIs were highlighted by the MM/GBSA free energy decomposition. The molecular visualization was supported by 3Dmol.js. For the structural modeling of PPIs, HawkDock could achieve a better performance than ZDOCK 3.0.2 in the benchmark testing. For the prediction of key residues, the important residues that play an essential role in PPIs could be identified in the top 10 residues for ∼81.4% predicted models and ∼95.4% crystal structures in the benchmark dataset. To sum up, the HawkDock server is a powerful tool to predict the binding structures and identify the key residues of PPIs. The HawkDock server is accessible free of charge at http://cadd.zju.edu.cn/hawkdock/.

scholarly journals In Silico Mutagenesis Based Remodeling of SARs-CoV-1 Peptide (ATLQAIAS) to Inhibit SARs-CoV-2: Structural-dynamics and Free Energy Calculations

2020 ◽  
Author(s):  
Abbas Khan ◽  
Shaheena Umbreen ◽  
Asma Hameed ◽  
Rida Fatima ◽  
Ujala Zahoor ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
In Silico ◽  
Therapeutic Potential ◽  
Decomposition Analysis ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Energy Calculation ◽  
Binding Affinities ◽  
The World

Abstract Background:The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. To date efforts are continuing to design small molecule inhibitor, vaccines and many other therapeutic options are practiced but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedure. Results:Hence, here we have repurposed a small peptide (ATLQAIAS) from the previous study which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residues energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at residue level. Conclusion:Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARs-CoV-2-borne pneumonia. Our analysis strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.

Small-to-Large Length Scale Transition of TMAO Interaction with Hydrophobic Solutes

2021 ◽  
Author(s):  
Angelina Folberth ◽  
Swaminath Bharadwaj ◽  
Nico van der Vegt
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Length Scale ◽  
Simulation Data ◽  
Energy Calculations ◽  
Large Length ◽  
Hydrophobic Solutes ◽  
Large Length Scale

We report the effect of trimethylamine N-oxide (TMAO) on the solvation of nonpolar solutes in water studied with molecular dynamics (MD) simulations and free-energy calculations. The simulation data indicate the...

Physical origin underlying the prenucleation-cluster-mediated nonclassical nucleation pathways for calcium phosphate

2019 ◽  
Vol 21 (27) ◽  
pp. 14530-14540 ◽  
Author(s):  
Xiao Yang ◽  
Mingzhu Wang ◽  
Yang Yang ◽  
Beiliang Cui ◽  
Zhijun Xu ◽  
...  
Keyword(s):  
Free Energy ◽  
Phase Separation ◽  
Calcium Phosphate ◽  
Molecular Mechanism ◽  
Free Energy Calculations ◽  
Nucleation Process ◽  
Physical Origin ◽  
Energy Calculations

We employed free energy calculations to reveal the molecular mechanism underlying the non-classical nucleation process and phase separation for calcium phosphate.

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