吲唑脲类辣椒素受体通道拮抗剂的定量构效关系

QSAR studies on indazolyl urea TRPV1 channel antagonists.

研究了吲唑脲类辣椒素受体(TRPV1)通道拮抗剂的定量构效关系(QSAR).首先,采用1H-吲唑异构形式,对27个TRPV1通道拮抗剂分子进行了HF/6-31G*水平上的结构优化,在优化结构上进行了5类拓扑指数和分子静电势及其导出参数的计算.运用多元线性回归方法对这些化合物的生物活性与其分子结构参数进行了关联.对所有化合物采用另一异构形式重复上述过程,以探讨互变异构对QSAR建模的影响.结果表明:互变异构对QSAR结果具有一定的影响,采用1H-吲唑异构形式得到的模型,在质量上均高于采用2H-吲唑异构体,预示着1H-吲唑异构体更有可能是吲唑脲类分子的活性异构形式;分子表面静电势参数结合GETAWAY参数可以较好地用于描述TRPV1通道拮抗剂分子结构与其活性间的定量关系.

The present paper is devoted to the study of quantitative structure-activity relationship（QSAR） for indazolyl ureas as TRPV1 antagonists.First,ab initio calculations have been performed at the HF/6-31G＊ level of theory for 27 indazolyl urea compounds（using 1H-indazole tautomeric form）.On the basis of optimized structures,five kinds of topological indices,electrostatic potentials as well as their statistically-drived quantities have been obtained.Linear correlations between the biological activities and the structural descriptors have been established by using multiple linear regression method.Then,by using another tautomer（2H-indazole form）,all of the above processes were repeated to investigate the effect of tautomerism upon the QSAR modelling.It has been shown that tautomerism has a significant effect on the QSAR modelling,and the models obtained from 1H-indazol tautomeric form always represent higher quality than those from 2H-indazol tautomer,which indicates that 1H-indazol tautomer of the indazolyl urea is probably the active form when binding with the TRPV1 channel protein.It has also been demonstrated that the theoretical descriptors derived from electrostatic potentials on molecular surface together with the GETAWAY descriptors can be well used to express the quantitative structure-activity relationship of indazolyl urea TRPV1 channel antagonists.