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.

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.

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...

scholarly journals Molecular Docking and Molecular Dynamics Studies on Selective Synthesis of α-Amyrin and β-Amyrin by Oxidosqualene Cyclases from Ilex Asprella

2019 ◽  
Vol 20 (14) ◽  
pp. 3469 ◽  
Author(s):  
Zhixue Wu ◽  
Hui Xu ◽  
Meiling Wang ◽  
Ruoting Zhan ◽  
Weiwen Chen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Selective Synthesis ◽  
Total Production ◽  
Oxidosqualene Cyclases ◽  
Free Energy Decomposition

Amyrins are the immediate precursors of many pharmaceutically important pentacyclic triterpenoids. Although various amyrin synthases have been identified, little is known about the relationship between protein structures and the constituent and content of the products. IaAS1 and IaAS2 identified from Ilex asprella in our previous work belong to multifunctional oxidosqualene cyclases and can produce α-amyrin and β-amyrin at different ratios. More than 80% of total production of IaAS1 is α-amyrin; while IaAS2 mainly produces β-amyrin with a yield of 95%. Here, we present a molecular modeling approach to explore the underlying mechanism for selective synthesis. The structures of IaAS1 and IaAS2 were constructed by homology modeling, and were evaluated by Ramachandran Plot and Verify 3D program. The enzyme-product conformations generated by molecular docking indicated that ASP484 residue plays an important role in the catalytic process; and TRP611 residue of IaAS2 had interaction with β-amyrin through π–σ interaction. MM/GBSA binding free energy calculations and free energy decomposition after 50 ns molecular dynamics simulations were performed. The binding affinity between the main product and corresponding enzyme was higher than that of the by-product. Conserved amino acid residues such as TRP257; TYR259; PHE47; TRP534; TRP612; and TYR728 for IaAS1 (TRP257; TYR259; PHE473; TRP533; TRP611; and TYR727 for IaAS2) had strong interactions with both products. GLN450 and LYS372 had negative contribution to binding affinity between α-amyrin or β-amyrin and IaAS1. LYS372 and ARG261 had strong repulsive effects for the binding of α-amyrin with IaAS2. The importance of Lys372 and TRP612 of IaAS1, and Lys372 and TRP611 of IaAS2, for synthesizing amyrins were confirmed by site-directed mutagenesis. The different patterns of residue–product interactions is the cause for the difference in the yields of two products.

scholarly journals Effect of mutations on binding of ligands to guanine riboswitch probed by free energy perturbation and molecular dynamics simulations

2019 ◽  
Vol 47 (13) ◽  
pp. 6618-6631 ◽  
Author(s):  
Jianzhong Chen ◽  
Xingyu Wang ◽  
Laixue Pang ◽  
John Z H Zhang ◽  
Tong Zhu
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Drug Targets ◽  
Md Simulations ◽  
Free Energy Perturbation ◽  
Potential Drug ◽  
Free Energy Decomposition ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Potential Drug Targets

Abstract Riboswitches can regulate gene expression by direct and specific interactions with ligands and have recently attracted interest as potential drug targets for antibacterial. In this work, molecular dynamics (MD) simulations, free energy perturbation (FEP) and molecular mechanics generalized Born surface area (MM-GBSA) methods were integrated to probe the effect of mutations on the binding of ligands to guanine riboswitch (GR). The results not only show that binding free energies predicted by FEP and MM-GBSA obtain an excellent correlation, but also indicate that mutations involved in the current study can strengthen the binding affinity of ligands GR. Residue-based free energy decomposition was applied to compute ligand-nucleotide interactions and the results suggest that mutations highly affect interactions of ligands with key nucleotides U22, U51 and C74. Dynamics analyses based on MD trajectories indicate that mutations not only regulate the structural flexibility but also change the internal motion modes of GR, especially for the structures J12, J23 and J31, which implies that the aptamer domain activity of GR is extremely plastic and thus readily tunable by nucleotide mutations. This study is expected to provide useful molecular basis and dynamics information for the understanding of the function of GR and possibility as potential drug targets for antibacterial.

scholarly journals Fast and Flexible GPU Accelerated Binding Free Energy Calculations within the AMBER Molecular Dynamics Package

2018 ◽  
Author(s):  
Daniel J. Mermelstein ◽  
Lin Charles ◽  
Nelson Gard ◽  
Kretsch Rachael ◽  
J. Andrew McCammon ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Graphics Processing Units ◽  
Early Stage ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Design And Optimization ◽  
Time Required

AbstractAlchemical free energy calculations (AFE) based on molecular dynamics (MD) simulations are key tools in both improving our understanding of a wide variety of biological processes and accelerating the design and optimization of therapeutics for numerous diseases. Computing power and theory have, however, long been insufficient to enable AFE calculations to be routinely applied in early stage drug discovery. One of the major difficulties in performing AFE calculations is the length of time required for calculations to converge to an ensemble average. CPU implementations of MD based free energy algorithms can effectively only reach tens of nanoseconds per day for systems on the order of 50,000 atoms, even running on massively parallel supercomputers. Therefore, converged free energy calculations on large numbers of potential lead compounds are often untenable, preventing researchers from gaining crucial insight into molecular recognition, potential druggability, and other crucial areas of interest. Graphics Processing Units (GPUs) can help address this. We present here a seamless GPU implementation, within the PMEMD module of the AMBER molecular dynamics package, of thermodynamic integration (TI) capable of reaching speeds of >140 ns/day for a 44,907-atom system, with accuracy equivalent to the existing CPU implementation in AMBER. The implementation described here is currently part of the AMBER 18 beta code and will be an integral part of the upcoming version 18 release of AMBER.

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