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Identifying Effective Antiviral Drugs Against SARS-Cov-2 by Drug Repositioning Through Virus-Drug Association Prediction

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Identifying Effective Antiviral Drugs Against SARS-Cov-2 by Drug Repositioning Through Virus-Drug Association Prediction fgene-11-577387 September 14, 2020 Time: 15:45 # 1 ORIGINAL RESEARCH published: 16 September 2020 doi: 10.3389/fgene.2020.577387 Identifying Effective Antiviral Drugs Against SARS-CoV-2 by Drug Repositioning Through Virus-Drug Association Prediction Lihong Peng1*†, Xiongfei Tian1†, Ling Shen1, Ming Kuang1, Tianbao Li2, Geng Tian2, Jialiang Yang2* and Liqian Zhou1* 1 School of Computer Science, Hunan University of Technology, Zhuzhou, China, 2 Geneis (Beijing) Co., Ltd., Beijing, China A new coronavirus called SARS-CoV-2 is rapidly spreading around the world. Over 16,558,289 infected cases with 656,093 deaths have been reported by July 29th, 2020, and it is urgent to identify effective antiviral treatment. In this study, potential antiviral drugs against SARS-CoV-2 were identified by drug repositioning through Virus- Edited by: Drug Association (VDA) prediction. 96 VDAs between 11 types of viruses similar Wei Lan, to SARS-CoV-2 and 78 small molecular drugs were extracted and a novel VDA Guangxi University, China identification model (VDA-RLSBN) was developed to find potential VDAs related to Reviewed by: Qi Zhao, SARS-CoV-2. The model integrated the complete genome sequences of the viruses, Liaoning University, China the chemical structures of drugs, a regularized least squared classifier (RLS), a bipartite Weiyang Chen, local model, and the neighbor association information. Compared with five state-of- Qilu University of Technology, China the-art association prediction methods, VDA-RLSBN obtained the best AUC of 0.9085 *Correspondence: Lihong Peng and AUPR of 0.6630. Ribavirin was predicted to be the best small molecular drug, [email protected] with a higher molecular binding energy of −6.39 kcal/mol with human angiotensin- Jialiang Yang − [email protected] converting enzyme 2 (ACE2), followed by remdesivir ( 7.4 kcal/mol), mycophenolic Liqian Zhou acid (−5.35 kcal/mol), and chloroquine (−6.29 kcal/mol). Ribavirin, remdesivir, and [email protected] chloroquine have been under clinical trials or supported by recent works. In addition, † These authors have contributed for the first time, our results suggested several antiviral drugs, such as FK506, with equally to this work molecular binding energies of −11.06 and −10.1 kcal/mol with ACE2 and the spike Specialty section: protein, respectively, could be potentially used to prevent SARS-CoV-2 and remains This article was submitted to to further validation. Drug repositioning through virus–drug association prediction can Computational Genomics, a section of the journal effectively find potential antiviral drugs against SARS-CoV-2. Frontiers in Genetics Keywords: SARS-CoV-2, antiviral drugs, drug repositioning, virus-drug association, regularized least square, Received: 29 June 2020 bipartite local model, neighbor association information Accepted: 18 August 2020 Published: 16 September 2020 Citation: INTRODUCTION Peng L, Tian X, Shen L, Kuang M, Li T, Tian G, Yang J and Zhou L Last December 2019, a novel coronavirus called SARS-CoV-2 by the World Health (2020) Identifying Effective Antiviral Organization (WHO), first found in Wuhan, China, was rapidly spreading around the Drugs Against SARS-CoV-2 by Drug Repositioning Through Virus-Drug world (Kaiser et al., 2020; Sanche et al., 2020). The SARS-CoV-2 outbreak was declared Association Prediction. as a global public health emergency by WHO, and a total of 16,558,289 cases have Front. Genet. 11:577387. been confirmed with another 656,093 deaths throughout the world by July 29th, 2020 doi: 10.3389/fgene.2020.577387 (World Health Organization [WHO], 2020). SARS-CoV-2 caused a severe acute respiratory Frontiers in Genetics| www.frontiersin.org 1 September 2020| Volume 11| Article 577387 fgene-11-577387 September 14, 2020 Time: 15:45 # 2 Peng et al. VDA-RLSBN syndrome named COVID-19, and no special vaccine or antiviral (Wishart et al., 2018), NCBI (Sayers et al., 2020), and PubMed ori drug against SARS-CoV-2 has been found at present (Lu, 2020; (Canese and Sarah, 2013) databases. The element yij in the VDA Wang et al., 2020c). Therefore, finding a special antiviral drug as matrix Yori 2 <n×m was represented as soon as possible is urgent to stop the spread of SARS-CoV-2 (Lu, 2020; Zhang et al., 2020a). 1 if the ith virus associates with the jth drug yori D (1) However, designing a new drug to treat COVID-19 in a ij 0 otherwise short time is almost impossible (Zhang et al., 2020a). One of the best strategies is drug repositioning (Chen et al., 2012, These similar viruses included SARS-CoV (Ding et al., 2004), 2016; Peng et al., 2017a; Beck et al., 2020). By repositioning MERS-CoV (Groot et al., 2013), human immunodeficiency virus already commercialized drugs, the undesired effects can be type 1 (Wei et al., 1995) and type 2 (Guyader et al., 1987) inferred to find new uses for these drugs. This strategy can (HIV-1 and HIV-2), chronic hepatitis C virus (HCV) (Jacobson thus greatly shorten the time required for an antiviral drug et al., 2011), influenza A viruses [A-H1N1 (Kumar et al., 2009), against SARS-CoV-2. A-H5N1 (Subbarao et al., 1998), A-H7N9 (Gao et al., 2013)], Although little is known about SARS-CoV-2, its complete Hendra virus (Bonaparte et al., 2005), human cytomegalovirus genome sequence is strongly homologous to SARS-CoV (Huang (Cobbs et al., 2002), and respiratory syncytial virus (Hall, 2001). et al., 2020; Morse et al., 2020). Therefore, in this study, to Complete genome sequences of these 11 viruses and SARS-CoV- prioritize available FDA-approved antiviral drugs against SARS- 2 were downloaded from the NCBI database, and virus similarity 2 <n×n COV-2 for further clinical trials, 11 well-studied viruses similar matrix Sv was computed based on MAFFT, a multiple- to SARS-CoV-2 were selected and 96 virus–drug associations sequence alignment software. Chemical structures of drugs were (VDAs) with these 11 viruses were integrated. Regularized downloaded from the DrugBank database, and drug similarity 2 <m×m least squared classifier (RLS), bipartite local model (BLM), matrix Sd was obtained by RDKit, an open-source and neighbor association information were applied in our new cheminformatics tool. The details are shown in Table 1. algorithm named VDA-RLSBN to find novel VDAs for new virus (especially for SARS-CoV-2) or new drug. The results showed Methods that ribavirin, remdesivir, and chloroquine may be antiviral drugs Problem Formalization against SARS-CoV-2. Bleakley and Yamanishi(2009) represented a drug–target Molecular docking techniques investigate the behavior of interaction network as a bipartite graph and developed a BLM- small molecular drugs in the binding site of a target protein. based method to predict possible drug–target interactions. The As more target protein structures are confirmed experimentally, proposed method first inferred targets of a given FDA-approved molecular docking approaches are widely applied to drug design drug and drugs targeting a known protein and then combined (Zhang et al., 2020b). AutoDock (Goodsell et al., 1996; Ruyck these two independent predictions. The results demonstrated et al., 2016) is an available software applied to identify the bound the excellent performance of BLM. Similar to the drug–target conformations of a small molecular drug to a macromolecular interaction network, the VDA network can also be taken as target. The AutoDock affinity scoring function is applied to rank a bipartite graph. Results in this study are thus presented to the candidate poses based on the sum of the van der Waals evaluate the prediction performance in each of the following four and electrostatic energies. We conducted molecular docking cases for a given putative virus–drug pair: between the predicted top 10 antiviral drugs against SARS-CoV-2 • The virus with at least one known drug and the drug with and two target proteins including the spike protein of SARS- at least one known virus. CoV-2 and human angiotensin-converting enzyme 2 (ACE2) • The virus with at least one known drug and the drug molecule (Wang et al., 2020a). The molecular binding energies without any known virus (new drug). between the above three drugs and ACE2 are ribavirin with • The virus without any known drug (new virus) and the drug −6.39 kcal/mol, remdesivir with −7.4 kcal/mol, and chloroquine with at least one known virus. with −6.29 kcal/mol. These three small molecules have been • New virus and new drug. under clinical trial or supported by recent publications. In addition, we found that FK506 shows higher molecular binding Based on these four cases, we represent a VDA network as a pre energies of −10.1 kcal/mol and −11.06 kcal/mol with these bipartite graph and thus the predicted VDA matrix Yn×m can be two targets, which suggest that FK506 may be applied to stop COVID-19 although there is no report about its association with SARS-CoV-2. TABLE 1 | Statistics of viruses and drugs. Virus No. of drugs Virus No. of drugs MATERIALS AND METHODS SARS-CoV 15 Hendra virus 1 MERS-CoV 9 HIV-1 35 Dataset A-H1N1 4 HIV-2 3 Aiming at identifying potential VDAs related to SARS-CoV-2, A-H5N9 2 HCV 15 96 known VDAs between 11 viruses similar to SARS-CoV-2 A-H7N9 4 Respiratory syncytial virus 2 and 78 small molecular drugs were selected from the DrugBank Human cytomegalovirus 6 SARS-CoV-2 0 Frontiers in Genetics| www.frontiersin.org 2 September 2020| Volume 11| Article 577387 fgene-11-577387 September 14, 2020 Time: 15:45 # 3 Peng et al. VDA-RLSBN denoted as Eq. (2): predict associations between new viruses and new drugs. To solve this problem, we developed a VDA prediction model pre .Y1/ncv×mcv .Y2/ncv×m N (VDA-RLSBN) by integrating neighbor association information Yn×m D (2) .Y3/nN×mcv .Y4/nN×m N into the RLS model.
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