【作者】 梁娜娜；

【导师】 葛志强；

【作者基本信息】 天津大学 ， 制药工程， 2008， 硕士

【摘要】 PTP-1B作为治疗Ⅱ型糖尿病的新靶点已引起人们广泛关注,寻找和开发该酶的特异性抑制剂成为近年来该领域研究的热点。PTP-1B与TCPTP在催化区域的同源性高达80%,而且抑制PTP-1B的化合物大都对TCPTP也表现出相同的抑制作用。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,具有很好的药用开发前景。为了探讨该类化合物在PTP-1B和TCPTP之间选择性存在显著差异的分子机制,首先采用分子对接(FlexX)的方法,对该类化合物与PTP-1B和TCPTP的相互作用方式进行了比较研究。然后通过CoMFA和CoMSIA两种方法对该类化合物的结构与抑制活性之间的定量关系(QSAR)进行了研究,为设计高选择性的苯并三唑类PTP-1B抑制剂奠定了基础。最后通过建立QSSR模型,对该类化合物的结构与选择性之间的定量关系进行了研究,为设计高选择性的苯并三唑类PTP-1B抑制剂指引了方向。结果发现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。综合以上结果可以看出,能够提高化合物抑制活性的取代基并不一定能够提高化合物的选择性。因此今后对苯并三唑类化合物的设计,应综合考虑以上因素,从而设计出活性更高、选择性也更高的苯并三唑类PTP-1B抑制剂。更多还原

【Abstract】 PTP-1B has recently received much attention as a potential drug target in type 2 diabetes, and selective PTP-1B inhibitors could be of significant therapeutic utility. Several groups have reported structurally diverse PTP-1B inhibitors with a good selectivity profile over other PTPs, but generally not over TCPTP. Because TCPTP has an 80% homology to PTP-1B in the catalytic domains, and non-selective inbition gives rise to severe side effects. Benzotriazole derivatives were found to be potent PTP-1B inhibitors, and provide a moderate degree of selectivity for PTP-1B over TCPTP. Molecular docking studies were performed using FlexX in order to find the different molecular mechanism between PTP-1B and TCPTP. The 3D-QSAR and 3D-QSSR studies were conducted by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA), and provied the useful information to improve the inhibitory activity and selectivity. Based on the docking conclusions, the hydrogen bond formed between Arg24 in PTP-1B and the molecular is of great importance to enhance the selectivity. The obtained models with the best predictions showed that bulky, negatively charged and hydrogen-bond donor groups at R2 position would increase the inhibitory activity, and bulky, positively charged and hydrogen-bond acceptor groups at the end of the R2 position would increase the selectivity. Sum of the above conclusions, the substitute which could increase inhibitory activity did not necessarily increased the selectivity. Therefore, we must consider all the factors to design new benzotriazole derivatives as PTP-1B inhibitors in future.更多还原