scholarly journals Efficient estimation of binding free energies between peptides and an MHC class II molecule using coarse-grained molecular dynamics simulations with a weighted histogram analysis method

2017 ◽  
Vol 38 (23) ◽  
pp. 2007-2019 ◽  
Author(s):  
Ming Huang ◽  
Wenjun Huang ◽  
Fei Wen ◽  
Ronald G. Larson
Keyword(s):  
Molecular Dynamics ◽  
Mhc Class Ii ◽  
Efficient Estimation ◽  
Coarse Grained ◽  
Analysis Method ◽  
Free Energies ◽  
Dynamics Simulations ◽  
Weighted Histogram ◽  
Weighted Histogram Analysis ◽  
Binding Free Energies

Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

2014 ◽  
Vol 92 (9) ◽  
pp. 821-830 ◽  
Author(s):  
Zhi-Guang Zhou ◽  
Qi-Zheng Yao ◽  
Dong Lei ◽  
Qing-Qing Zhang ◽  
Ji Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Biological Activities ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

Virtual Screening-Based Discovery of Potent Hypoglycemic Agents: In Silico, Chemical Synthesis and Biological Study

2019 ◽  
Vol 15 ◽  
Author(s):  
Mohammed A. Khedr ◽  
Omar M. M. Mohafez ◽  
Ibrahim A. Al-Haider
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Hypoglycemic Agents ◽  
Type Ii ◽  
Free Energies ◽  
Diabetes Mellitus Type Ii ◽  
Dynamics Simulations ◽  
Binding Free Energies

Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II. Objective: The main aim of this study is to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action. Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations was done to evaluate the binding stability of resulted hits. Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4-substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold that were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds. Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

Computational insight into the mechanisms of action and selectivity of Afraxis PAK inhibitors

2020 ◽  
Vol 12 (5) ◽  
pp. 367-385
Author(s):  
Di Han ◽  
Huiqun Wang ◽  
Wei Cui ◽  
Beibei Zhang ◽  
Bo-Zhen Chen
Keyword(s):  
Molecular Dynamics ◽  
Mechanisms Of Action ◽  
Structural Basis ◽  
Free Energies ◽  
Activity Data ◽  
Experimental Activity ◽  
Inhibitory Mechanisms ◽  
Dynamics Simulations ◽  
Insight Into ◽  
Binding Free Energies

Aim: The p21-activated kinases (PAKs) are involved in many important biological activity regulations. FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 were identified as PAKs inhibitors. Their detailed inhibitory mechanisms deserve further investigation. Results: Molecular dynamics simulations and further calculations for the PAK1/inhibitor and PAK4/inhibitor complexes indicate that their binding free energies are basically consistent with the trend of experimental activity data. Conclusion: The anchoring of residues Leu347PAK1 and Leu398PAK4 is the structural basis for designing Afraxis PAK inhibitors. This study discloses the inhibitory mechanisms of FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 toward PAK1 and PAK4 and some clues to enhance kinase activities and selectivities, which will provide valuable information to the development of more potent and selective PAK inhibitors.

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