Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach.

Jing-Wei Wu, Huan Zhang, Wei-Ya Li, Xue Tang, Hong-Lian Li, Xin-Hua Lu, Zhi-Hui Zheng, Ying Ma, Run-Ling Wang

Journal of biomolecular structure & dynamics 2020 Nov

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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.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 WaalsCommunicated by Ramaswamy H. Sarma.

Citation

Jing-Wei Wu, Huan Zhang, Wei-Ya Li, Xue Tang, Hong-Lian Li, Xin-Hua Lu, Zhi-Hui Zheng, Ying Ma, Run-Ling Wang. Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach. Journal of biomolecular structure & dynamics. 2020 Nov;38(18):5338-5348