多药效团组合筛选PDE4B抑制剂研究.docVIP

 多药效团组合筛选 PDE4B 抑制剂研究# 王元明1，张燕玲1，乔延江2** （1. 北京中医药大学中药学院，北京 100102； 5 10 15 20 25 30 35 40 2. 北京中医药大学中药学院， 北京 100102） 摘要：本文以 17 个 PDE4B 受体-抑制剂复合物为研究对象，应用 LigandScout 构建了 17 个 药效团模型，并以多药效团组合筛选方法开展中药中具有 PDE4B 亚型选择性抑制活性成分 的辨识研究。本文中经过配体再匹配和已知活性化合物数据库筛选两种评价方法，评价并 保留了 17 个药效团模型；以分子被命中频次作为多药效团组合筛选方法的综合性评价指 标，结合 MDDR 数据库筛选结果，确定了 PDE4B 抑制剂被命中大于或等于 8 次的分子为多 药效团组合筛选目标。本文比较了最优药效团筛选方法与多药效团组合筛选方法的筛选效 率，结果表明多药效团组合筛选方法的富集度和活性化合物有效命中率都比最优药效团筛 选方法高，分别为 38.017、47.44%，表明基于受体的多药效团组合筛选方法具有一定的可 靠性，有助于开展中药中有效成分的辨识研究。本文利用多药效团组合筛选方法开展了中 药化学成分数据库中 PDE4B 抑制剂筛选，筛选结果为进一步开展 PDE4B 抑制剂研究提供 了指导。 关键词：中药化学；磷酸二酯酶 4B；基于受体药效团；多药效团组合筛选；综合性评价指 标 中图分类号：O641 Combinatorial Screening PDE4B inhibitors base on multiple pharmacophores WANG Yuanming, ZHANG Yanling, QIAO Yanjiang (School of Chinese materia medica, Beijing University of Chinese Medicine, Beijing 100102) Abstract: Seventeen receptor-based pharmacophore models of phosphodiesterase 4B (PDE4B) inhibitor were generated by LigandScout base on seventeen PDE4B receptor-inhibitor complexes. The potential PDE4B selective inhibitors were identified from the Traditional Chinese Medicine (TCM) with the method of combinatorial screening with the seventeen models. By re-fitting with the ligand and screening MDL Drug Data Report (MDDR, Version 20072), seventeen pharmacophores were evaluated. Based on the screening results of MDDR, hit frequency of molecules was defined as the comprehensive appraisal index of combinatorial screening, and the molecules hit by not less than eight pharmacophores were taken as the screening objects of PDE4B inhibitor. The screening efficiency by the best pharmacophore and combination of multiple pharmacophores was compared. The result showed that the enrichment and percentage of the actives in the hit list of combinatorial screening were better than the best pharmacophore screening, which was 38.017 and 47.44% respectively. The results showed that combinatorial screening method of receptor-based multiple pharmacophores is reliabili