Liu Wen-Shan, Wang Rui-Rui, Yue Hai, Zheng Zhi-Hui, Lu Xin-Hua, Wang Shu-Qing, Dong Wei-Li, Wang Run-Ling
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.
Inner Mongolia Institute for Drug Control, Huhhot, Inner Mongolia, China.
J Biomol Struct Dyn. 2020 Aug;38(13):3814-3824. doi: 10.1080/07391102.2019.1664333. Epub 2019 Sep 19.
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1B and PTP1B systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBBblood-brain barrierCDC25Bcell division cycle 25 homolog BCYP2D6Cytochrome P450 2D6 bindingDCCMdynamic cross-correlation mapDSDiscovery StudioH bondhydrogen bondHIAhuman intestinal absorptionLARleukocyte antigen-related phosphataseMDmolecular dynamicsMEG-2maternal-effect germ-cell defective 2MM-PBSAmolecular mechanics Poisson Boltzmann surface area)PCAprincipal component analysisPDBProtein Data BankpNPPp-nitrophenyl phosphatePPBplasma protein bindingPTP1Bprotein tyrosine phosphotase 1BRMSDroot mean square deviationRMSFroot mean square fluctuationSHP-1src homologous phosphatase-1SHP-2src homologous phosphatase-2SPCsingle-point chargeTCPTPT cell protein tyrosine phosphataseT2DMType 2 diabetes mellitusVDWvan der WaalsCommunicated by Ramaswamy H. Sarma.
蛋白酪氨酸磷酸酶1B（PTP1B）是胰岛素信号通路的关键负调节因子，越来越多的研究表明它是治疗2型糖尿病（T2DM）的潜在靶点。在本研究中，设计并合成了17种新型4-噻唑啉酮衍生物作为新型PTP1B抑制剂，ADMET预测证实这些化合物具有类药物性质。对这些化合物进行了酶活性实验，发现多种化合物对PTP1B蛋白具有良好的抑制活性和高选择性。其中，化合物7p表现出最佳的抑制活性，IC为0.92μM。探索了化合物7p与PTP1B蛋白的结合模式，揭示了其高效的原因。此外，对PTP1B和PTP1B系统的分子动力学模拟揭示了化合物7p在分子水平上对PTP1B蛋白的影响。总之，该研究首次报道4-噻唑啉酮衍生物作为新型PTP1B抑制剂对治疗T2DM具有良好的抑制活性和选择性，为PTP1B抑制剂的开发提供了更多选择。缩写词：BBB血脑屏障；CDC25B细胞分裂周期25同源物B；CYP2D6细胞色素P450 2D6结合；DCCM动态交叉相关图；DS发现工作室；H键氢键；HIA人肠道吸收；LAR白细胞抗原相关磷酸酶；MD分子动力学；MEG-2母体效应生殖细胞缺陷2；MM-PBSA分子力学泊松玻尔兹曼表面积；PCA主成分分析；PDB蛋白质数据库；pNPP对硝基苯磷酸酯；PPB血浆蛋白结合；PTP1B蛋白酪氨酸磷酸酶1B；RMSD均方根偏差；RMSF均方根波动；SHP-1src同源磷酸酶-1；SHP-2src同源磷酸酶-2；SPC单点电荷；TCPTPT细胞蛋白酪氨酸磷酸酶；T2DM2型糖尿病；VDW范德华力。由Ramaswamy H. Sarma通讯。
