Computational revelation of binding mechanisms of inhibitors to endocellular protein tyrosine phosphatase 1B using molecular dynamics simulations.

Abstract

Endocellular protein tyrosine phosphatase 1B (PTP1B) is one of the most promising target for designing and developing drugs to cure type-II diabetes and obesity. Molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy methods were applied to study binding differences of three inhibitors (ID: 901, 941, and 968) to PTP1B, the calculated results show that the inhibitor 901 has the strongest binding ability to PTP1B among the current inhibitors. Principal component (PC) analysis was also carried out to investigate the conformational change of PTP1B, and the results indicate that the associations of inhibitors with PTP1B generate a significant effect on the motion of the WPD-loop. Free energy decomposition method was applied to study the contributions of individual residues to inhibitor bindings, it is found that three inhibitors can generate hydrogen bonding interactions and hydrophobic interactions with different residues of PTP1B, which provide important forces for associations of inhibitors with PTP1B. This research is expected to give a meaningfully theoretical guidance to design and develop of effective drugs curing type-II diabetes and obesity.

• Authors: Fangfang Yan, Xinguo Liu, Shaolong Zhang, Jing Su, Qinggang Zhang, Jianzhong Chen
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 36 Issue 14 Pg. 3636-3650 (Nov 2018) ISSN: 1538-0254 [Electronic] England
• PMID: 29048995 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Algorithms
• Binding Sites
• Catalytic Domain
• Hydrogen Bonding
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Principal Component Analysis
• Protein Binding
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, chemistry)
• Quantitative Structure-Activity Relationship