文献类型：期刊文献

英文题名：A Rapid Python-Based Methodology for Target-Focused Combinatorial Library Design

作者：Li, Shiliang[1];Song, Yuwei[1];Liu, Xiaofeng[1];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2016

卷号：19

期号：1

起止页码：25

外文期刊名：COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000368910000004)】；

基金：This work was supported by the 863 Hi-Tech Program of China (grant 2012AA020308), the National Natural Science Foundation of China (grants 81102375, 21173076, 81230090, 81222046 and 81230076), and the National S&T Major Project of China (Grant 2011ZX09307-002-03). Honglin Li is also sponsored by Shanghai Rising-Star Tracking Program (grant 13QH1401100), the Innovation Program of Shanghai Municipal Education Commission (grant 13SG32) and Fok Ying Tung Education Foundation (141035).

语种：英文

外文关键词：3D molecular similarity; chemical space; focused library design; product-based; reaction-based; SMILES

摘要：The chemical space is so vast that only a small portion of it has been examined. As a complementary approach to systematically probe the chemical space, virtual combinatorial library design has extended enormous impacts on generating novel and diverse structures for drug discovery. Despite the favorable contributions, high attrition rates in drug development that mainly resulted from lack of efficacy and side effects make it increasingly challenging to discover good chemical starting points. In most cases, focused libraries, which are restricted to particular regions of the chemical space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug discovery and drug development pipeline. This paper presented a valid methodology for fast target-focused combinatorial library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000 molecules per second. Simple, quick and convenient operating procedures are the specific features of the method. SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This rapid library enumeration method is portable and applicable to any other targets for good chemical starting points identification collaborated with either structure-based or ligand-based virtual screening.