Tan Xiaoqin, Jiang Xiangrui, He Yang, Zhong Feisheng, Li Xutong, Xiong Zhaoping, Li Zhaojun, Liu Xiaohong, Cui Chen, Zhao Qingjie, Xie Yuanchao, Yang Feipu, Wu Chunhui, Shen Jingshan, Zheng Mingyue, Wang Zhen, Jiang Hualiang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2020 Oct 15;204:112572. doi: 10.1016/j.ejmech.2020.112572. Epub 2020 Jul 12.
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, serotonin 5-HT and 5-HT 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.
诸如精神分裂症等复杂的神经精神疾病需要能够靶向多种G蛋白偶联受体（GPCR）以调节复杂神经精神功能的药物。在此，我们报告了一种由深度循环神经网络（RNN）和多任务深度神经网络（MTDNN）组成的自动化系统，用于设计和优化多靶点抗精神病药物。该系统已成功生成具有所需多种靶点活性的新型分子结构，其中合成了排名靠前的化合物3，并证明其对多巴胺D、5-羟色胺5-HT和5-HT受体具有强效活性。基于MTDNN进行了命中扩展，对化合物3的6种类似物进行了实验评估，其中化合物8不仅表现出特定的多药理学特征，而且在动物模型中显示出抗精神病作用，且镇静和僵住症的可能性较低，突出了它们适合进一步的临床前研究。该方法可以成为设计具有多靶点特征的先导化合物以在治疗复杂神经精神疾病中实现所需疗效的有效工具。
