几种改进的CoMFA方法比较研究血小板活化因子拮抗剂

Comparison of Modified CoMFAs in Study of PAF Antagonist

由于传统的比较分子场分析(CoMFA)方法本身存在一些缺陷,使得分子的叠合规则以及叠合分子的空间取向和空间位置等因素对q^2的影响很大,因此相继提出了几种改进的CoMFA方法.为了优化CoMFA结果,应用传统的CoMFA方法和交叉验证的R^2引导的区域选择法(q^2-GRS)、全取向搜索法(AOS)、全空间搜索法(APS)以及比较分子相似性指数(CoMSIA)等四种改进的CoMFA方法,对18个pinusolide类衍生物这类新发现的血小板活化因子(PAF)拮抗剂进行了比较研究.结果表明四种改进的CoMFA方法得到的q^2值均比传统CoMFA的高.q^2-GRS方法得到的q^2值有所提高,但综合结果并不理想,AOS与APS得到的q^2较为理想,而在CoMSIA中,q^2几乎不受空间取向或空间位置的影响.同时我们引入基于样本的偏最小二乘法(SAMPLS)取代原AOS/APS程序中的传统PLS进行统计分析,明显提高了其运行速度.最后,根据q^2最高的CoMFA模型和CoMSIA模型设计了几个预测活性更高的pinusolide类似物.

Traditional comparative molecular field analysis (CoMFA) has some critical problems. It is found that, except for alignment rule, the change in overall orientation or placement of the same set of aligned molecules can cause great variation in q2 . Several protocols have been developed to optimize q2 and improve the predictability of CoMFA. In the present study we used conventional CoMFA and introduced four routines of modified CoMFA, cross-validated R2-guided regional selection ( q2-GRS), all-orientation search (AOS), all-placement search (APS) and comparative molecular similarity indices analysis (CoMSIA) , to investigate a set of 18 pinusolide and its derivatives as a kind of newly discovered platelet activating factor (PAF) antagonist. The results reveal that the q2 values obtained by the four modified CoMFA are all better than that of conventional CoMFA. AOS/APS ones lead to the highest q2 of 0.813 and 0.615 for dataset 1 and 2, respectively. CoMSIA is hardly sensitive to the overall orientation or placement as expected. We significantly improved the calculating speed of AOS/APS by using sample-distance partial least square (SAMPLS) instead of originally used conventional PLS and suggested that the improved AOS/APS and CoMSIA could be routinely used in the future CoMFA studies to guarantee the reproducibility of the reported q2 values.