文献类型：期刊文献

英文题名：X-ray Structure and Molecular Docking Guided Discovery of Novel Chitinase Inhibitors with a Scaffold of Dipyridopyrimidine-3-carboxamide

作者：Yuan, Pengtao[1];Jiang, Xi[2];Wang, Siyu[2];Shao, Xusheng[1,3];Yang, Qing[2];Qian, Xuhong[1,3,4]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[2]Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Guangdong Lab Lingnan Modern Agr, Shenzhen Branch, Shenzhen 518120, Peoples R China;[3]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]East China Normal Univ, Sch Chem & Mol Engn, Shanghai 200241, Peoples R China

年份：2020

卷号：68

期号：47

起止页码：13584

外文期刊名：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY

收录：;EI(收录号：20204909564672);WOS:【SCI-EXPANDED(收录号:WOS:000595545400026)】；

基金：This work was financially supported by the Key Project of the Shanghai Science and Technology Committee (18DZ1112703), the National Natural Science Foundation of China (31830076), and the Shenzhen Science and Technology Program (KQTD20180411143628272).

语种：英文

外文关键词：chitinase; inhibitor; X-ray structure; pest control

摘要：Chitinases are the glycosyl hydrolase for catalyzing the degradation of chitin and play an indispensable role in bacterial pathogenesis, fungal cell wall remodeling, and insect molting. Thus, chitinases are attractive targets for therapeutic drugs and pesticides. Here, we present a strategy of developing a novel chemotype of chitinase inhibitors by the construction of planar heterocycles that can stack with conserved aromatic residues. The rational design, guided by crystallographic analysis and docking results, leads to a series of dipyridopyrimidine-3-carboxamide derivatives as chitinase inhibitors. Among them, compound 6t showed the most potent activity against bacterial chitinase SmChiB and insect chitinase Of Chi-h, with a K-i value of 0.14 and 0.0056 mu M, respectively. The strong stacking interaction of compound 6p with Trp99 and Trp220 found in the SmChiB-6p co-crystal structure verifies the feasibility of our design. Our results provide novel insights into developing potent chitinase inhibitors for pathogen and pest control.