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Flexible scaffold-based cheminformatics approach for polypharmacological drug design

文献类型：期刊论文

作者Chen, Zhangcheng7; Yu, Jing7; Wang, Huan6; Xu, Peiyu1,5; Fan, Luyu4; Sun, Fengxiu7; Huang, Sijie5; Zhang, Pei7; Huang, He3; Gu, Shuo3
刊名CELL
出版日期2024-04-25
卷号187期号:9页码:38
ISSN号0092-8674
DOI10.1016/j.cell.2024.02.034
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Cheng, Jianjun(chengjj@shanghaitech.edu.cn) ; Wang, Sheng(wangsheng@sibcb.ac.cn)
英文摘要Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold -based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down"binding pose at 5-HT 2A R to act as an antagonist and a "stretching-up"binding pose at 5-HT 1A R to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT 2A R for psychoactive symptoms and activating 5-HT 1A R to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter"and "conformation shaper,"which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.
WOS关键词ATYPICAL ANTIPSYCHOTIC-DRUG ; STRUCTURE-BASED DISCOVERY ; RECEPTOR ; SEROTONIN ; LIGANDS ; MODEL ; MICE ; SCHIZOPHRENIA ; GENERATION ; PARADIGM
资助项目Third Research Institute of the Ministry of Public Security (China) ; National Natural Science Foundation of China[32071197] ; National Natural Science Foundation of China[22177074] ; National Natural Science Foundation of China[22377077] ; National Natural Science Foundation of China[2023TQ0353] ; Ministry of Science and Technology of China[2020YFA0509102] ; Shanghai Science and Technology Committee[19ZR1466200] ; Shanghai Science and Technology Committee[20S11901200] ; Program of Shanghai Academic/Technology Research Leader[22XD1421900] ; Shanghai Municipal Government ; ShanghaiTech University ; Youth Innovation Promotion Association, CAS
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001234158100001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/311791]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Cheng, Jianjun; Wang, Sheng
作者单位1.MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.ComMedX, Beijing 100094, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
7.Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Key Lab Multicell Syst,Shanghai Inst Biochem & Cel, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Zhangcheng,Yu, Jing,Wang, Huan,et al. Flexible scaffold-based cheminformatics approach for polypharmacological drug design[J]. CELL,2024,187(9):38.
APA Chen, Zhangcheng.,Yu, Jing.,Wang, Huan.,Xu, Peiyu.,Fan, Luyu.,...&Wang, Sheng.(2024).Flexible scaffold-based cheminformatics approach for polypharmacological drug design.CELL,187(9),38.
MLA Chen, Zhangcheng,et al."Flexible scaffold-based cheminformatics approach for polypharmacological drug design".CELL 187.9(2024):38.

入库方式： OAI收割

来源：上海药物研究所

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