4,6,17取代6氮杂4烯3酮甾体类5α还原酶抑制剂构效关系的量子化学研究
构效关系,,药物化学;构效关系;AM1量子化学方法;甾体5α还原酶抑制剂,1.1构象优化和电子结构的计算
摘 要 目的 探寻甾体类5α还原酶抑制剂电子结构与活性的关系。方法 应用分子力学MM+法、量子化学AM1法对15个4,6,17取代甾体类5α还原酶抑制剂进行构象优化,计算了化合物的电子结构指数,并应用逐步回归探寻化合物量化指数和活性的关系。结果 ①本组化合物的HOMO、LUMO主要分布在母环A环和B环的C3位到N6位这一区域以及O21位上;②疏水常数logP与药效的关系为非线性关系;③得到较显著的QSAR方程。结论 ①从HOMO的分布角度指出分子的4,6位置可能是与酶作用的活性区域;②解释了疏水常数logP与药效的关系为非线性关系的原因;③研究讨论分子的电子结构与药效的关系。关键词 药物化学;构效关系;AM1量子化学方法;甾体5α还原酶抑制剂
Study of structureactivity relationships for 4,6substituted 6azaandrost4en3ones of 5αreductase Inhibitors with quantum chemistry
GAO Wei,XU Xuan
(1.Department of Pharmacy,Guangdong College of Pharmacy,Guangzhou 510240,China; 2.Department of Chemistry,South China Normal University, Guangzhou 510631,China)
Abstract Objective To analyze the structureactivity relationships of 4,6,17substituted 6azaandrost4en3ones of 5αreductase inhibitors. Methods To calculate and study by use of molecular mechanics MM+ and quantum chemistry methods AM1, the methods of stepwise regression had been performed. Results ①The component of HOMO and LUMO mainly distributed from C3 to N6 and O21 on the ring A,B; ②logP affects the activity in a nonlinear way; ③The significant QSAR model was set up. Conclusion ①Sites at 4, 6 are the possible active area where compounds interact with enzyme from distribution of HOMO. ②The reason for logP affected the activity in a nonlinear way was explained. ③We discussed the structureactivity relationships. ......
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