Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach
Creators: name: Wu, Jing-Wei
name: Zhang, Huan
name: Li, Wei-Ya
name: Tang, Xue
name: Li, Hong-Lian
name: Lu, Xin-Hua
name: Zheng, Zhi-Hui
name: Ma, Ying
name: Wang, Run-Ling
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: 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 (IC<sub>50</sub>=44.40 μM), SHP2 (IC<sub>50</sub>&gt;122.81 μM) and CDC25B (IC<sub>50</sub>&gt;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. AbbreviationsPTP-LARHuman leukocyte common antigen-relatedPTPProtein Tyrosine PhosphataseIRinsulin receptorPTP1BProtein tyrosine phosphatase-1BLRPLung resistance proteinADMETabsorption, distribution, metabolism, excretion, toxicityPPBplasma protein bindingBBBblood brain barrier penetrationCYP450cytochrome P450HIAhuman intestinal absorptionTLCthin-layer chromatographyUVUltra VioletNMRnuclear magnetic resonanceTMStetramethylsilaneMSmass spectrometryANManisotropic network modePDBProtein Data BankDMFN,N-DimethylformamidepNPPpara-nitrophenyl phosphateDTTdithiothreitolMDmolecular dynamicRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationSPCsingle-point chargePMEParticle Mesh EwaldMM-PBSAmolecular mechanics Poisson Boltzmann surface areaH bond, hydrogen bondVDWVan der Waals Human leukocyte common antigen-related Protein Tyrosine Phosphatase insulin receptor Protein tyrosine phosphatase-1B Lung resistance protein absorption, distribution, metabolism, excretion, toxicity plasma protein binding blood brain barrier penetration cytochrome P450 human intestinal absorption thin-layer chromatography Ultra Violet nuclear magnetic resonance tetramethylsilane mass spectrometry anisotropic network mode Protein Data Bank N,N-Dimethylformamide para-nitrophenyl phosphate dithiothreitol molecular dynamic root-mean-square deviation root-mean-square fluctuation single-point charge Particle Mesh Ewald molecular mechanics Poisson Boltzmann surface area , hydrogen bond Van der Waals Communicated by Ramaswamy H. Sarma