Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Rafv600E inhibitors  

作　　者：Gui-min WANG Xiang WANG Jian-ming ZHU Bin-bin GUO Zhuo YANG Zhi-jian XU Bo LI He-yao WANG Ling-hua MENG Wei-liang ZHU Jian DING 

机构地区：[1]CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]University of Chinese Academy of Sciences, Beijing 100049, China [3]National Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2017年第7期1059-1068,共10页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （81273435, 81302699 and 81321092）, the National Science and Technology Major Project （2013ZX09103001001）, the Ministry of Science and Technology （2012AA01A305）, the Natural Science Foundation of Shanghai, China （14ZR1447800）, the State Key Laboratory of Natural and Biomimetic Drugs （K20150205） and the Special Program for Applied Research on Super Computation of the NSFC-Guang- dong Joint Fund （the second phase）.

摘　　要：The mutation of B-Rafv600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Rafv600E is an ideal drug target. This study focused on developing novel B-Rafv600E inhibitors as drug leads against various cancers with B-Rafv600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Rafv600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Rafv600E inhibitors. A highly potent fragment binding to the hinge area of B-Rafv600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Rafv600E inhibitors. Biological evaluation revealed that compound lm is a potent B-Rafv600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib （0.13 μmol/L）. Moreover, the selectivity of lm against B-RafwT was enhanced compared with vemurafenib. In addition, lm exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays, Thus, a highly potent and selective B-Rafv600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.The mutation of B-Rafv600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Rafv600E is an ideal drug target. This study focused on developing novel B-Rafv600E inhibitors as drug leads against various cancers with B-Rafv600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Rafv600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Rafv600E inhibitors. A highly potent fragment binding to the hinge area of B-Rafv600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Rafv600E inhibitors. Biological evaluation revealed that compound lm is a potent B-Rafv600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib （0.13 μmol/L）. Moreover, the selectivity of lm against B-RafwT was enhanced compared with vemurafenib. In addition, lm exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays, Thus, a highly potent and selective B-Rafv600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

关 键 词：B-Rafv600E inhibitor anticancer VEMURAFENIB deazapurine fragment reassembly molecular docking STRUCTURE-ACTIVITYRELATIONSHIP 

分 类 号：TQ463.5[化学工程—制药化工] Q615[生物学—生物物理学]