Prediction of anti-EGFR drug resistance base on binding free energy and hydrogen bond analysis

2013 ◽  
Author(s):  
Weiqiang Zhou ◽  
Debby D. Wang ◽  
Hong Yan ◽  
Maria Wong ◽  
Victor Lee
Keyword(s):  
Hydrogen Bond ◽  
Drug Resistance ◽  
Free Energy ◽  
Binding Free Energy ◽  
Hydrogen Bond Analysis

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.

scholarly journals Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation

2019 ◽  
Vol 19 (2) ◽  
pp. 461
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Thomas S Hofer ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Inhibition Mechanism ◽  
Energy Calculation ◽  
Protein Receptor ◽  
The Stability

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions

RSC Advances ◽  
2016 ◽  
Vol 6 (63) ◽  
pp. 58573-58585 ◽  
Author(s):  
Jianzhong Chen
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Binding Free Energy ◽  
Resistance Mechanisms ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Probe Drug ◽  
Dynamics Simulations ◽  
Hiv 1

Molecular dynamics simulation and binding free energy calculations were used to probe drug resistance of HIV-1 protease mutations toward inhibitors.

scholarly journals Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 920
Author(s):  
Qinfang Sun ◽  
Ronald M. Levy ◽  
Karen A. Kirby ◽  
Zhengqiang Wang ◽  
Stefan G. Sarafianos ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Energy Cost ◽  
Binding Free Energy ◽  
Resistance Mutation ◽  
Side Chain ◽  
Ligand Interaction ◽  
Energy Simulations ◽  
Hiv 1

While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.

Molecular Characterization of Avermectin that Bind to Rdl β5 GABA Receptors of House Fly

2013 ◽  
Vol 699 ◽  
pp. 753-758 ◽  
Author(s):  
Ming Hao ◽  
Qiang Wang ◽  
Qing Qing Ma ◽  
Jin Long Zhao ◽  
Wan Guo Hou ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Characterization ◽  
Hydrophobic Interaction ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Binding Free Energy ◽  
House Fly ◽  
Before And After

The interaction between Rdlβ5 GABA receptors of house fly before and after mutation and AVM was considered as the reason that AVM cause the insect death and investigated with Sybylx1.1 software. The docking results showed that the hydrogen bond and hydrophobic interaction played an important role among the complexes of Rdlβ5 GABA receptor and avermectin. Hydrogen bond of 2.217 Å formed between B/Ser58 of GABA receptor and atom O42 of avermectin before mutation, 1.953 Å hydrogen bond formed between A/Gln6 of GABA receptor and hydroxyl (C7) of avermectin after mutation. In addition, our results indicated that the binding free energy (ΔE) of AVM and GABA receptors increased 3.59 kcal mol−1 after mutation, which was consistent with the experimental phenomenon of the insecticidal resistance to AVM.

scholarly journals Stability, Hydrogen Bond Occupancy Analysis and Binding Free Energy Calculation from Flavonol Docked in DAPK1 Active Site Using Molecular Dynamic Simulation Approaches

2020 ◽  
Author(s):  
Adi Tiara Zikri ◽  
Harno Dwi Pranowo ◽  
Winarto Haryadi
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Energy Calculation ◽  
Compound C ◽  
C Complex

Stability and hydrogen bond occupancy analysis of flavonol derivative docked in DAPK1 have been carried out using molecular dynamics simulation approach. Six flavonol derivatives were docked in DAPK1 as protein target, then continued with molecular dynamics simulation. NVT and NPT ensembles were used to equilibrate the system, followed by 20 ns sampling time for each system. Structural stability and hydrogen bond occupancy analyses were carried out at the NVT ensemble, while free binding energy analysis was done at NPT ensemble. From all compounds used in this work, compound B (5,7-dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one) has a similar interaction with reference ligands (quercetin, kaempferol, and fisetin), and the most stable complex system has the maximum RMSD around 2 Å. Compound C complex has -48.06 kJ/mol binding free energy score, and it was slightly different from quercetin, kaempferol, and fisetin complexes. Even though complex C has similar binding free energy with the reference compound, complex B shows more stable interactions due to their hydrogen bond and occupancy.

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