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 μM) over its close homolog PTP1B (IC50 =44.40 μM), SHP2 (IC50 >122.81 μM) and CDC25B (IC50 >122.81 μM) 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. Abbreviations: PTP-LAR, Human leukocyte common antigen-related; PTP, Protein Tyrosine Phosphatase; IR,  insulin receptor; PTP1B, Protein tyrosine phosphatase-1B; LRP, Lung resistance protein; ADMET, absorption, distribution, metabolism, excretion, toxicity; PPB, plasma protein binding; BBB, blood brain barrier penetration; CYP450, cytochrome P450; HIA, human intestinal absorption; TLC, thin-layer chromatography; UV, Ultra Violet; NMR, nuclear magnetic resonance; TMS, tetramethylsilane; MS, mass spectrometry; ANM, anisotropic network mode; PDB, Protein Data Bank; DMF, N,N-Dimethylformamide; pNPP, para-nitrophenyl phosphate; DTT, dithiothreitol; MD, molecular dynamic; RMSD, root-mean-square deviation; RMSF, root-mean-square fluctuation; SPC, single-point charge; PME, Particle Mesh Ewald; MM-PBSA, molecular mechanics Poisson Boltzmann surface area; H bond, hydrogen bond; VDW, Van der Waals.