http://orcid.org/0000-0002-0285-3619
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Abstract
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 |
Communicated by Ramaswamy H. Sarma
Disclosure statement
There is no conflict of interest.
