Revealing the Unbinding Kinetics and Mechanism of Type I and Type II Protein Kinase Inhibitors by Local-Scaled Molecular Dynamics Simulations

2020 ◽  
Vol 16 (10) ◽  
pp. 6620-6632
Author(s):  
Yu Du ◽  
Renxiao Wang
Keyword(s):  
Molecular Dynamics ◽  
Protein Kinase ◽  
Molecular Dynamics Simulations ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Kinetics And Mechanism ◽  
Type I ◽  
Type Ii ◽  
Dynamics Simulations

scholarly journals A molecular dynamics simulation study on the propensity of Asn-Gly-containing heptapeptides towards β-turn structures: Comparison with ab initio quantum mechanical calculations

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243429
Author(s):  
Dimitrios A. Mitsikas ◽  
Nicholas M. Glykos
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Molecular Dynamics Simulations ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Type I ◽  
Quantum Mechanical Calculations ◽  
Water Solvent ◽  
Simulation Protocol ◽  
Dynamics Simulations

Both molecular mechanical and quantum mechanical calculations play an important role in describing the behavior and structure of molecules. In this work, we compare for the same peptide systems the results obtained from folding molecular dynamics simulations with previously reported results from quantum mechanical calculations. More specifically, three molecular dynamics simulations of 5 μs each in explicit water solvent were carried out for three Asn-Gly-containing heptapeptides, in order to study their folding and dynamics. Previous data, based on quantum mechanical calculations within the DFT framework have shown that these peptides adopt β-turn structures in aqueous solution, with type I’ β-turn being the most preferred motif. The results from our analyses indicate that at least for the given systems, force field and simulation protocol, the two methods diverge in their predictions. The possibility of a force field-dependent deficiency is examined as a possible source of the observed discrepancy.

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.

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