论文部分内容阅读
Aim:To investigate the dynamic properties of protein-tyrosine phosphatase (PTP)1B and reveal the structural factors responsible for the high inhibitory potencyand selectivity of the inhibitor SNA for PTP1B.Methods:We performed moleculardynamics (MD) simulations using a long time-scale for both PTP1B and PTP1Bcomplexed with the inhibitor SNA,the most potent and selective PTP1B inhibitorreported to date.The trajectories were analyzed by using principal componentanalysis.Results:Trajectory analyses showed that upon binding the ligand,theflexibility of the entire PTP1B molecule decreases.The most notable change is themovement of the WPD-loop.Our simulation results also indicated that electro-static interactions contribute more to PTP 1B-SNA complex conformation than thevan der Waals interactions,and that Lys41,Arg47,and Asp48 play important rolesin determining the conformation of the inhibitor SNA and in the potency andselectivity of the inhibitor.Of these,Arg47 contributed most.These results werein agreement with previous experimental results.Conclusion:The informationpresented 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 theactive phosphate binding site).
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 PTP1B.Methods: We performed molecular dynamics (MD) simulations using a long time-scale for both PTP1B and PTP1Bcomplexed with the inhibitor SNA, the most potent and selective PTP1B inhibitorreported to date. The trajectories were analyzed by using principal componental analysis. Results: Trajectory analyzes showing that upon binding the ligand, the flexibility of the entire PTP1B molecule decreases.The most it is not possible to change the activity of the WPD-loop. Our simulation results also show that electro-static 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 the severity of the inhibitor. Of these, Arg47 contributed most.These resu lts werein agreement with previous experimental results. Conlusion: The informationpresented 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).