Design Potential Selective Inhibitors For Human Leukocyte Common Antigen-Related (Ptp-Lar) With Fragment Replace Approach

The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 mu M) over its close homolog PTP1B (IC50=44.40 mu M), SHP2 (IC50>122.81 mu M) and CDC25B (IC50>122.81 mu M) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors.