An Efficient Modern Strategy to Screen Drug Candidates Targeting RdRp of SARS-CoV-2 With Potentially High Selectivity and Specificity

Zhang, Haiping1; Gong, Xiaohua2; Peng, Yun2; Saravanan, Konda Mani3; Bian, Hengwei4; Zhang, John Z. H.1; Wei, Yanjie5; Pan, Yi5; Yang, Yang2

2022-07-12

10.3389/fchem.2022.933102

Frontiers in Chemistry   影响因子和分区

2296-2646

Desired drug candidates should have both a high potential binding chance and high specificity. Recently, many drug screening strategies have been developed to screen compounds with high possible binding chances or high binding affinity. However, there is still no good solution to detect whether those selected compounds possess high specificity. Here, we developed a reverse DFCNN (Dense Fully Connected Neural Network) and a reverse docking protocol to check a given compound's ability to bind diversified targets and estimate its specificity with homemade formulas. We used the RNA-dependent RNA polymerase (RdRp) target as a proof-of-concept example to identify drug candidates with high selectivity and high specificity. We first used a previously developed hybrid screening method to find drug candidates from an 8888-size compound database. The hybrid screening method takes advantage of the deep learning-based method, traditional molecular docking, molecular dynamics simulation, and binding free energy calculated by metadynamics, which should be powerful in selecting high binding affinity candidates. Also, we integrated the reverse DFCNN and reversed docking against a diversified 102 proteins to the pipeline for assessing the specificity of those selected candidates, and finally got compounds that have both predicted selectivity and specificity. Among the eight selected candidates, Platycodin D and Tubeimoside III were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 619.5 and 265.5 nM, respectively. Our study discovered that Tubeimoside III could inhibit SARS-CoV-2 replication potently for the first time. Furthermore, the underlying mechanisms of Platycodin D and Tubeimoside III inhibiting SARS-CoV-2 are highly possible by blocking the RdRp cavity according to our screening procedure. In addition, the careful analysis predicted common critical residues involved in the binding with active inhibitors Platycodin D and Tubeimoside III, Azithromycin, and Pralatrexate, which hopefully promote the development of non-covalent binding inhibitors against RdRp.

antiviral agent RdRp compound specificity estimation virtual screening tubeimoside III

SCI

英语

通讯

National Science Foundation of China["62106253","21933010"] ; Shenzhen KQTD Project[KQTD20200820113106007] ; National Key Research and Development Program of China[2018YFB0204403] ; Strategic Priority CAS Project[XDB38000000]

Chemistry

Chemistry, Multidisciplinary

WOS:000831783300001

FRONTIERS MEDIA SA

Web of Science

1.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen Inst Synthet Biol, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Hosp 2, Natl Clin Res Ctr Infect Dis,Shenzhen Key Lab Path, Shenzhen, Peoples R China
3.Bharath Inst Higher Educ & Res, Dept Biotechnol, Chennai, India
4.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, Shanghai Key Lab Green Chem & Chem Proc, Shanghai, Peoples R China
5.Chinese Acad Sci, Shenzhen Inst Adv Technol, Ctr High Performance Comp, Joint Engn Res Ctr Hlth Big Data Intelligent Anal, Shenzhen, Peoples R China

Zhang, Haiping,Gong, Xiaohua,Peng, Yun,et al. An Efficient Modern Strategy to Screen Drug Candidates Targeting RdRp of SARS-CoV-2 With Potentially High Selectivity and Specificity[J]. Frontiers in Chemistry,2022,10.

Zhang, Haiping.,Gong, Xiaohua.,Peng, Yun.,Saravanan, Konda Mani.,Bian, Hengwei.,...&Yang, Yang.(2022).An Efficient Modern Strategy to Screen Drug Candidates Targeting RdRp of SARS-CoV-2 With Potentially High Selectivity and Specificity.Frontiers in Chemistry,10.

Zhang, Haiping,et al."An Efficient Modern Strategy to Screen Drug Candidates Targeting RdRp of SARS-CoV-2 With Potentially High Selectivity and Specificity".Frontiers in Chemistry 10(2022).