Automated design and optimization of multitarget schizophrenia drug candidates by deep learning | |
Tan, Xiaoqin2,3; Jiang, Xiangrui1; He, Yang1; Zhong, Feisheng2,3; Li, Xutong2,3; Xiong, Zhaoping2,4,5; Li, Zhaojun2,6; Liu, Xiaohong2,4,5; Cui, Chen2,3; Zhao, Qingjie1 | |
刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY |
2020-10-15 | |
卷号 | 204页码:16 |
关键词 | Schizophrenia Multitarget antipsychotic drugs Recurrent neural network Multitask deep neural network Automated drug design |
ISSN号 | 0223-5234 |
DOI | 10.1016/j.ejmech.2020.112572 |
通讯作者 | Zheng, Mingyue(myzheng@simm.ac.cn) ; Wang, Zhen(wangzhen@simm.ac.cn) ; Jiang, Hualiang(hljiang@simm.ac.cn) |
英文摘要 | Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitarget antipsychotic drugs. The system has successfully generated novel molecule structures with desired multiple target activities, among which high-ranking compound 3 was synthesized, and demonstrated potent activities against dopamine D-2, serotonin 5-HT1A and 5-HT2A receptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound 3 were evaluated experimentally, among which compound 8 not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases. (C) 2020 Elsevier Masson SAS. All rights reserved. |
资助项目 | National Natural Science Foundation of China[81773634] ; National Natural Science Foundation of China[81703338] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Personalized Medicinesd Molecular Signature based Drug Discovery and Development, Strategic Priority Research of the Chinese Academy of Sciences[XDA12050201] ; Personalized Medicinesd Molecular Signature based Drug Discovery and Development, Strategic Priority Research of the Chinese Academy of Sciences[XDA12040331] |
WOS关键词 | ANTIPSYCHOTIC-DRUGS ; DISCOVERY ; PHARMACOLOGY ; DISORDERS ; RECEPTORS ; LIBRARIES ; TARGETS ; UNIQUE |
WOS研究方向 | Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
WOS记录号 | WOS:000573916100012 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/291101] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Zheng, Mingyue; Wang, Zhen; Jiang, Hualiang |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Huaxiazhong Rd, Shanghai 200031, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Huaxiazhong Rd, Shanghai 200031, Peoples R China 6.Dezhou Univ, Sch Informat Management, 566 West Univ Rd, Dezhou 253023, Peoples R China |
推荐引用方式 GB/T 7714 | Tan, Xiaoqin,Jiang, Xiangrui,He, Yang,et al. Automated design and optimization of multitarget schizophrenia drug candidates by deep learning[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,204:16. |
APA | Tan, Xiaoqin.,Jiang, Xiangrui.,He, Yang.,Zhong, Feisheng.,Li, Xutong.,...&Jiang, Hualiang.(2020).Automated design and optimization of multitarget schizophrenia drug candidates by deep learning.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,204,16. |
MLA | Tan, Xiaoqin,et al."Automated design and optimization of multitarget schizophrenia drug candidates by deep learning".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 204(2020):16. |
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