基于糖皮质激素受体调节剂波尼松龙的定量构效关系研究

Study on quantitative structure-activity relationship of prednisolone derivativesas glucocorticoid receptor modulators

为了探讨糖皮质激素受体调节剂波尼松龙系列的结构和活性之间的关系,首次使用比较分子力场(CoMFA)和比较分子相似性指数分析(CoMSIA)方法对77个靶标分子建立三维定量构效关系(3D-QSAR)模型.在基于配体叠合的基础上,得到了最好的CoMSIA模型(Q2=0.504,R2ncv=0.849,SEE=0.283,F=56.365和R2pred=0.792).模型的三维等势线图分析说明了疏水性基团在R1取代基位置有利于提高活性,亲水性基团在R2取代基位置有利于提高活性.此外,分子对接分析结果显示了与波尼松龙形成一些氢键的氨基酸Asn564,Gln642,Thr739在糖皮质激素受体调节剂中有重要作用.本文得到的结果能够更好地帮助理解糖皮质激素受体调节剂作用机理,并为今后的药物设计与合成提供了新思路.

In order tO explore the structure-activity correlation of prednisolone series as glucocorticoid receptor modulators, a set of 3D-QSAR models were, for the first time, developed in the present work employing comparative molecular field analysis （CoMFA） and comparative molecular similarity indices analysis （CoMSIA） for 77 promising molecules. Based on the ligand-based alignment, an opti- mal 3D-QSAR model was obtained with good predictive power of Q2 = 0. 504, R2ncv = 0. 849, SEE = 0. 283, F=56. 365 and R2pred=0. 792. The 3D contour maps suggested that the hydrophobic group at the R1 position and hydrophilic groups at the R2 substituents position can enhance the activity. Fur- thermore, the docking analysis showed that Ash564, Gln642, Thr739 which formed several H-bonds with prednisolone are crucial for glucocorticoid receptor modulators. The obtained results from this study can provide useful information for better understanding of the mechanism of glucocorticoid re- ceptor modulators and also be helpful in providing new guidelines for drug design and synthesis.