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Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study

文献类型：期刊论文

作者Zhang, Fu-Mao2,3; Yuan, Liang1,4; Shi, Xin-Wei2,3; Feng, Kai-Rui5; Lan, Xiaojing4; Huang, Cheng2,3; Lin, Guo-Qiang2,3; Tian, Ping2,3; Huang, Min4,6; Tang, Shuai4,6
刊名BIOORGANIC CHEMISTRY
出版日期2022-04-01
卷号121页码:13
关键词Virtual screening PHGDH Structure-activity relationships Antitumor
ISSN号0045-2068
DOI10.1016/j.bioorg.2022.105705
通讯作者Tang, Shuai(tangshuai@simm.ac.cn) ; Gao, Dingding(gaodingding@shutcm.edu.cn)
英文摘要Phosphoglycerate dehydrogenase (PHGDH) is abnormally expressed in numerous malignant tumor cells and catalyzes the first step of serine biosynthesis, thus becoming a key drug target for antitumor treatment. In this study, compound B2 bearing a benzene-1,3-diamine scaffold was identified by structure-based virtual screening as a novel PHGDH inhibitor with moderate enzymatic activity. The structure-activity relationship study led to the discovery of compound C25 possessing improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. The enzyme kinetic assay confirmed that C25 inhibited PHGDH in a nicotinamide adenine dinucleotide (NAD(+)) competitive manner. Molecular docking and mutagenesis experiment on PHGDH collectively revealed the binding site and key interaction residues of C25 in the PHGDH catalytic site. Taken together, this study provides information on the structural diversity for a further development of potent PHGDH inhibitors.
WOS关键词SERINE BIOSYNTHESIS ; CANCER METABOLISM ; DRUG DISCOVERY ; DEHYDROGENASE ; IDENTIFICATION ; EXPRESSION ; PATHWAY
资助项目National Natural Science Foundation of China[81903423] ; National Natural Science Foundation of China[91957126] ; Shanghai Sailing Program[19YF1449300] ; Program of Shanghai Academic/Technology Research Leader[20XD1403600] ; Program of Shanghai Academic/Technology Research Leader[20XD1424800] ; Shanghai Municipal Education Commission[2019-01-07-00-10-E00072] ; Science and Technology Commission of Shanghai Municipality[20400750300] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000788738500006
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/299373]  
专题新药研究国家重点实验室
通讯作者Tang, Shuai; Gao, Dingding
作者单位1.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
2.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Weifang Med Univ, Sch Pharm, Weifang 261000, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Fu-Mao,Yuan, Liang,Shi, Xin-Wei,et al. Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study[J]. BIOORGANIC CHEMISTRY,2022,121:13.
APA Zhang, Fu-Mao.,Yuan, Liang.,Shi, Xin-Wei.,Feng, Kai-Rui.,Lan, Xiaojing.,...&Gao, Dingding.(2022).Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study.BIOORGANIC CHEMISTRY,121,13.
MLA Zhang, Fu-Mao,et al."Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study".BIOORGANIC CHEMISTRY 121(2022):13.

入库方式： OAI收割

来源：上海药物研究所

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