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Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor

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Aim: To investigate the dynamic properties of protein-tyrosine phosphatase (PTP) 1B and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTP 1B. Methods: We performed molecular dynamics (MD) simulations using a long time-scale for both PTP 1B and PTP 1B complexed with the inhibitor SNA, the most potent and selective PTP 1B inhibitor reported to date. The trajectories were analyzed by using principal component analysis. Results: Trajectory analyses showed that upon binding the ligand, the flexibility of the entire PTP1B molecule decreases. The most notable change is the movement of the WPD-loop. Our simulation results also indicated that electrostatic interactions contribute more to PTP 1B-SNA complex conformation than the van der Waals interactions, and that Lys41, Arg47, and Asp48 play important roles in determining the conformation of the inhibitor SNA and in the potency and selectivity of the inhibitor. Of these, Arg47 contributed most. These results were in agreement with previous experimental results. Conclusion: The information presented here suggests that potent and selective PTP 1B inhibitors can be designed by targeting the surface residues, for example the region containing Lys41, Arg47, and Asp48, instead of the second phosphate binding site (besides the active phosphate binding site).

Keywords: molecular dynamics simulation; principal component analysis; protein-tyrosine phosphatase 1B; type 2 diabetes

Document Type: Research Article


Affiliations: 1: Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 2: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Publication date: 2006-01-01

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