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

作　　者：Gui-xia LIU Jin-zhi TAN Chun-ying NIU Jian-hua SHEN Xiao-min LUO Xu SHEN Kai-xian CHEN Hua-liang JIANG 

机构地区：[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 andTechnology, Shanghai 200237, China

出　　处：《Acta Pharmacologica Sinica》2006年第1期100-110,共11页中国药理学报（英文版）

基　　金：Project supported by the State Key Program of Basic Research of China(No.2002CB512802);the National Natural Science Foundation of China(No.20372069,29725203,and 20072042);a Shanghai Science and Technology Commission Grant No 02DJ14006);the Key Project for New Drug Research from the Chinese Academy of Sciences;the National High Technology Research and Development Program of China(No 2002AA233061,2002AA104270,2002AA233011,and 2003AA235030);supported by the Foundation of East China University of Science and Technology for Research(No.YC0142101).

摘　　要：Aim： To investigate the dynamic properties of protein-tyrosine phosphatase （PTP） IB and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTPIB. Methods： We performed molecular dynamics （MD） simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B 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 PTPIB 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 PTP1B inhibitors can be de- signed 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）.Aim： To investigate the dynamic properties of protein-tyrosine phosphatase （PTP） IB and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTPIB. Methods： We performed molecular dynamics （MD） simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B 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 PTPIB 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 PTP1B inhibitors can be de- signed 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）.

关 键 词：molecular dynamics simulation principal component analysis protein-tyrosine phosphatase 1B type 2 diabetes 

分 类 号：R977.3[医药卫生—药品]