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蛋白酪氨酸磷酸酶1B(PTP-1B)特异性抑制剂是近年来治疗Ⅱ型糖尿病药物研发的热点.PTP-1B与T细胞蛋白酪氨酸磷酸酶(TCPTP)同源性很高,为了避免在使用PTP-1B抑制剂过程中对TCPTP产生交叉抑制,则需要设计开发对PTP-1B具有高活性和高特异选择性的小分子化合物.苯并三唑类化合物对PTP-1B的抑制活性很高,并且其中一些化合物对PTP-1B表现出了较好的特异选择性,具有良好的药用开发前景.通过CoMFA和CoMSIA两种方法分别对该类化合物进行了三维定量结构-活性关系(3D-QSAR)和三维定量结构-选择性关系(3D-QSSR)研究,并建立了相关的预测模型.计算结果表明PTP-1B中的Arg24与化合物的氢键相互作用是提高选择性的重要因素,并且在R2位引入氢键供体且体积较大的强供电子基团,将有利于化合物抑制活性的提高,而在R2位取代基的末端引入氢键受体且体积较大的强吸电子基团,将有利于化合物选择性的提高.
Protein tyrosine phosphatase 1B (PTP-1B) specific inhibitors in recent years, the treatment of type II diabetes drug development hot spots.PTP-1B and T cell protein tyrosine phosphatase (TCPTP) high homology, in order to To avoid the cross-inhibition of TCPTP during the use of PTP-1B inhibitors, it is necessary to design and develop small molecule compounds with high activity and high specificity for PTP-1B. The inhibitory activity of benzotriazole compounds against PTP-1B High, and some of them showed good specificity for PTP-1B and had good prospects for medicinal development.The three-dimensional structure-activity relationships of these compounds were investigated by CoMFA and CoMSIA respectively 3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR), and established the related prediction model.The results show that the hydrogen bond interaction between Arg24 and PTP-1B compounds is an important factor to improve the selectivity , And the introduction of hydrogen bond donors and larger bulky electron donor groups at the R2 position will favor the increase of compound inhibitory activity while introducing a bulky strong suction at the end of the R2 substituent Electronic groups, will help compound Selective increase.