scholarly journals Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3018 ◽  
Author(s):  
Gao Tu ◽  
Tingting Fu ◽  
Fengyuan Yang ◽  
Lixia Yao ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Computational Simulation ◽  
Critical Role ◽  
Dynamics Simulation ◽  
Peptide Docking ◽  
C Terminus ◽  
Free Energy Decomposition

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

MOLECULAR DYNAMICS AND FREE ENERGY ANALYSES OF ERK2–PYRAZOLYLPYRROLE INHIBITORS INTERACTIONS: INSIGHT INTO STRUCTURE-BASED LIGAND DESIGN

2009 ◽  
Vol 08 (05) ◽  
pp. 887-908 ◽  
Author(s):  
JIN-HUI ZHAN ◽  
XI ZHAO ◽  
XU-RI HUANG ◽  
CHIA-CHUNG SUN
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Signal Transduction Pathway ◽  
Binding Mode ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Protein Motions ◽  
Extracellular Signal

The extracellular signal-regulated protein kinase 2 (ERK2) is a pivotal member involving in Ras/Raf/MEK/ERK signal transduction pathway, acting as a central point where multiple signaling pathways coalesce to drive transcription. The pyrazolylpyrrole compounds as ATP competitive inhibitors of ERK2 can bind target with a special binding mode and have higher inhibitory potency than other ERK2-inhibitors. We investigated the interaction mode of ERK2-inhibitor using molecular dynamics simulation. The molecular mechanics Poisson–Boltzmann surface area approach is used to calculate the binding free energy of ERK2 with pyrazolylpyrrole inhibitors to analyze the factors of improving the affinity. The results indicated that the electrostatic interactions play the most important role in keeping the stabilization of ERK2-inhibitor. The structural analyses showed that the protein motions can be controlled by changing the structures of inhibitors; furthermore, the full use of available space in the binding site by improving the flexibilities of inhibitors and introducing hydrophobic groups can increase the inhibitory effect.

Virtual Compound Screening and Molecular Dynamics to Identify New Inhibitors for Human Glutathione Reductase

2020 ◽  
Vol 17 (12) ◽  
pp. 1465-1474
Author(s):  
Mohsen Sargolzaei
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Glutathione Reductase ◽  
Binding Free Energy ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Reductase Inhibitors ◽  
Free Energy Decomposition

Background: Oxidative stress is a defense mechanism against malarial intracellular parasite infection. On the other hand, the Human glutathione reductase enzyme reduces oxidative stress in the cells, making the inhibitors of this enzyme a promising candidate for malaria treatment. Objective: Rational drug design was used in this work to plan new human glutathione reductase inhibitors. Methods: Virtual screening was performed using the ZINC database and molecular docking was used to detect appropriate human glutathione reductase inhibitors. Based on the docking scores obtained, the top three highest-ranked ligands were selected for the molecular dynamics simulation study. The MD simulation was performed for each complex in a length of 100 ns. Results: RMSD, RMSF and hydrogen bond analyzes were performed on the derived trajectories. Molecular mechanics generalized born surface area (MM-GBSA) and pairwise per-residue free energy decomposition analyzes were performed for the determination of binding free energy and the determination of dominant residues involved in the binding process, respectively. The binding free energy analysis showed that the molecule of 3-((7-(furan-2-ylmethyl)-5,6-diphenyl-7H-pyrrolo[2,3- d] pyrimidin-4-yl) amino) propan-1-ol is the most potent inhibitor among the molecules considered against human glutathione reductase enzyme. Conclusion: This molecule can be considered a novel candidate for antimalarial treatments.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

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