以次黄嘌呤脱氢酶为靶点的抗病毒化合物的虚拟筛选及活性研究  

Virtual screening and activity study of antiviral compounds targeting inosine 5'-monophosphate dehydrogenase

作　　者：寇世博 高荣梅[1] 易红[1] 孙连奇 李玉环[1] 李卓荣[1] KOU Shi-bo;GAO Rong-mei;YI Hong;SUN Lian-qi;LI Yu-huan;LI Zhuo-rong(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院,医药生物技术研究所,北京100050

出　　处：《药学学报》2022年第10期3011-3018,共8页Acta Pharmaceutica Sinica

基　　金：中国医学科学院医学与健康科技创新工程项目(CAMS,2021-I2M-1-030)。

摘　　要：次黄嘌呤脱氢酶(inosine 5'-monophosphate dehydrogenase,IMPDH)是催化生物体内核苷酸从头合成途径限速步骤的关键酶。近年来,它已成为抗病毒、抗癌、抗菌、抗寄生虫等多种疾病的治疗靶标。研究表明,IMPDH抑制剂可以通过耗竭宿主细胞内病毒复制所需原料鸟苷酸(GMP),有效抑制病毒在宿主细胞的增殖,具有广谱抗病毒特性。为了寻找和发现新型抗冠状病毒药物,本研究基于IMPDH蛋白结构,利用分子对接与ROC计算进行虚拟筛选,从70000个天然小分子库中筛选出22个潜在的IMPDH抑制剂。以利巴韦林为阳性对照药,采用Huh7细胞、H460细胞模型,对筛选出来的22个目标化合物的抗冠状病毒HCoV-229E和HCoV-OC43活性进行验证,其中化合物11、12、15、16对HCoV-229E毒株有抑制活性;化合物4、12、13、15对HCoV-OC43毒株具有不同程度的抑制活性。化合物12和15对两种实验病毒株都有明显的抑制活性,药效与利巴韦林相当,可以作为IMPDH抑制剂先导化合物进行深入研究。Inosine 5'-monophosphate dehydrogenase(IMPDH)is a key enzyme catalyzing the rate-limiting step of de novo nucleotide synthesis in vivo.In recent years,it has become a therapeutic target for anti-virus,antibacterial,anti-cancer,anti-parasitic and other diseases.IMPDH inhibitors have been shown to inhibit viral proliferation in host cells by depleting guanosine 5'-monophosphate(GMP),the raw material required for viral replication in host cells,with broad-spectrum antiviral properties.In order to find novel anti-coronavirus drugs,this study screened 22 potential IMPDH inhibitors from 70000 natural small molecule libraries based on IMPDH protein structure using molecular docking and ROC calculation for virtual screening.With ribavirin as the positive control drug,Huh7 cell and H460 cell models were used to verify the anti-coronavirus HCoV-229E and HCoV-OC43 activities of 22 selected target compounds.Among them,compounds 11,12,15 and 16 showed inhibitory activity against coronavirus HCoV-229E.The compounds 4,12,13 and 15 showed inhibitory activities against coronavirus HCoVOC43.12 and 15 showed significant inhibitory activity against both two coronaviruses,and their efficacy was similar to ribavirin at the same dose,which can be further studied as a lead compound for IMPDH inhibitors.

关 键 词：次黄嘌呤脱氢酶 抑制剂 分子对接 冠状病毒 活性筛选 

分 类 号：R967[医药卫生—药理学]