【作者】 李剑； 张键； 陈静； 贵春山； 柳红； 沈旭； 蒋华良； 陈凯先；

【Author】 LI Jian, ZHANG Jian, CHEN Ling, GUI Chun-shan, LIU Hong, SHEN Xu, JIANG Hua-liang, CHEN Kai-xian Drug Design and Discovery Center, Shanghai Institute of Meteria Medica, Chinese Academy of Sciences, Shanghai 201203

【机构】 中国科学院上海药物研究所药物发现与设计中心；

【摘要】 目的:设计、合成亲环素A抑制剂并研究与亲环素A的结合活性和肽脯氨酰顺反异构酶的抑制活性。方法分两个阶段进行:(1)运用分子对接模式(采用DOCK 4．0)对SPECS小分子商业数据库进行虚拟筛选和类药性分析,购买排名靠前的分子,采用SPR技术在BIAcore 3000上测试与亲环素A的结合常数,挑选结合活性强的化合物进行合成及衍生化改造,测试所有合成化合物与亲环素A的结合常数,及其肽脯氨酰顺反异构酶抑制活性;(2)根据以上活性结果,挑选活性较好的化合物和一些已报道的药效团构建碎片库,自建的亲环素A抑制剂的组合集中库。采用相同的方法对集中库进行虚拟筛选,合成及活性测试。结果共合成56个新化合物,所有目的化合物结构均经1H-NMR,MS 和HRMS确证。大部分目的化合物具有较强的亲环素A结合活性,9个目的化合物具有较强的肽脯氨酰顺反异构酶抑制活性。结论将基于结构的虚拟筛选和基于碎片的化合物库设计运用于新药发现研究,结合化学合成和生物测试发现了具有亲环素A抑制活性的化合物。更多还原

【Abstract】 OBJECTIVE To design and synthesize Cyclophilin A (CypA) inhibitors and study their binding affinities to CypA and peptidyl prolyl cis-trans isomerases (PPIases) inhibition activities. METHODS Divided into two steps; (1) Employing the DOCK4.0 program and our own filter of druglikeness, we screened on the SPECS database. Those molecules with the highest score were purchased and determined their bindng affinities to CypA in vitro by employing the surface plasmon resonance (SPR) technology (using Biacore 3000 instrument). Those compounds with potent binding affinities were selected and structurally modified. The binding affinities to CypA and PPIases inhibition activities against CypA of all synthesized compounds were tested. (2) According to the above results along with our previously discovered pharmacophore of CypA inhibitors, we designed a CypA-focused combinatorial library. Using the above way, vitual screening on the focused library, synthsis and bioassay were achieved respectively. RESULTS Fifty-six compounds were synthesized. The chemical structures were determined by 1H-NMR, MS and HRMS. Most compounds could bind to CypA in vitro, nine compounds could inhibited the PPIase activity of CypA. CONCLUSION our approach, structure-based virtual screening, fragment-based drug design combining with chemical synthesis and bioassay, is used successfully in discovering potent inhibitors against CypA.更多还原