高效镇痛剂羟甲芬太尼药效构象的系统分析

A SYSTEMATIC CONFORMATION SEARCH FOR OHMEFENTANYL A HIGH-POTENCY ANALGESIC AGENT

本文用合理简化的系统搜索方法研究了柔性化合物羟甲芬太尼的构象性质，使用分子力学ＭＭＰ２程序，以（３Ｒ，４Ｓ，２０Ｒ）－羟甲芬太尼的Ｘ－射线晶体参数作为起始结构，通过能量优化得到该化合物的六个最低能量构象；在此基础上进一步研究了活性最高异构体（３Ｒ，４Ｓ，２０Ｓ）－羟甲芬太尼的低能构象。对比二者的低能构象推测出羟甲芬太尼两个可能的活性构象，（３Ｒ，４Ｓ，２０Ｒ）－羟甲芬太尼晶体中呈现的构象可能并不是该化合物的活性构象。依据所推测的活性构象和药效基团，可进一步设计新化合物分子，以提高药物的药效强度和选择性，

The conformations of ohmefentanyl,a flexible compound which poccesses highly analgesic potency,were analyzed using a simplified systematic search strategy. MMP2 was used in the conformation optimization and energy calculation. Starting from the known X-ray crystallographic structure,six energetically most favorable conformations of(3R,4S,20R)-ohmefentanyl were determined.The energetically most favorable conformations of its most active stereo-isomer-(3R,4S,20S)-ohmefentanyl,whose X-ray structure is not available yet,were also determined.The possible active conformations of ohmefentanyl were deduced,which help design more potent compounds and increase the selectivity for the μ-opioid receptor.