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(COVID-19) Through Virtual Screening Targeting SARS-Cov-2 Main Protease

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(COVID-19) Through Virtual Screening Targeting SARS-Cov-2 Main Protease biology Article Drug Repurposing Approach against Novel Coronavirus Disease (COVID-19) through Virtual Screening Targeting SARS-CoV-2 Main Protease Kamrul Hasan Chowdhury 1,†, Md. Riad Chowdhury 1,†, Shafi Mahmud 2, Abu Montakim Tareq 1 , Nujhat Binte Hanif 1, Naureen Banu 1, A. S. M. Ali Reza 1,* , Talha Bin Emran 3,* and Jesus Simal-Gandara 4,* 1 Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh; [email protected] (K.H.C.); [email protected] (M.R.C.); [email protected] (A.M.T.); [email protected] (N.B.H.); [email protected] (N.B.) 2 Microbiology Laboratory, Bioinformatics Division, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; shafi[email protected] 3 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh 4 Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo–Ourense Campus, E32004 Ourense, Spain * Correspondence: [email protected] (A.S.M.A.R.); [email protected] (T.B.E.); [email protected] (J.S.-G.) † These authors contributed equally to this work. Simple Summary: With the urgent necessity of potential treatment against novel coronavirus disease, we used several computational methods to search for active drugs from an extensive database. The results of our investigation suggested several established drugs that can be subjected to further analysis for the treatment of novel coronavirus disease. Various methods used in this study proved the effectiveness of the retrieved drugs. Therefore, our findings highly recommend the mentioned drugs to be scrutinized to discover drugs against novel coronavirus. Citation: Chowdhury, K.H.; Chowd- hury, M.R.; Mahmud, S.; Tareq, A.M.; Abstract: Novel coronavirus disease (COVID-19) was identified from China in December 2019 Hanif, N.B.; Banu, N.; Reza, A.S.M.A.; and spread rapidly through human-to-human transmission, affecting so many people worldwide. Emran, T.B.; Simal-Gandara, J. Drug Until now, there has been no specific treatment against the disease and repurposing of the drug. Repurposing Approach against Novel Our investigation aimed to screen potential inhibitors against coronavirus for the repurposing of Coronavirus Disease (COVID-19) through drugs. Our study analyzed sequence comparison among SARS-CoV, SARS-CoV-2, and MERS-CoV to Virtual Screening Targeting SARS-CoV- pro 2 Main Protease. Biology 2021, 10, 2. determine the identity matrix using discovery studio. SARS-CoV-2 M was targeted to generate an https://dx.doi.org/10.3390/ E-pharmacophore hypothesis to screen drugs from the DrugBank database having similar features. biology10010002 Promising drugs were used for docking-based virtual screening at several precisions. Best hits from virtual screening were subjected to MM/GBSA analysis to evaluate binding free energy, followed by Received: 23 November 2020 the analysis of binding interactions. Furthermore, the molecular dynamics simulation approaches Accepted: 19 December 2020 were carried out to assess the docked complex’s conformational stability. A total of 33 drug classes Published: 23 December 2020 were found from virtual screening based on their docking scores. Among them, seven potential drugs with several anticancer, antibiotic, and immunometabolic categories were screened and showed Publisher’s Note: MDPI stays neu- promising MM/GBSA scores. During interaction analysis, these drugs exhibited different types of tral with regard to jurisdictional claims hydrogen and hydrophobic interactions with amino acid residue. Besides, 17 experimental drugs in published maps and institutional selected from virtual screening might be crucial for drug discovery against COVID-19. The RMSD, affiliations. RMSF, SASA, Rg, and MM/PBSA descriptors from molecular dynamics simulation confirmed the complex’s firm nature. Seven promising drugs for repurposing against SARS-CoV-2 main pro- tease (Mpro), namely sapanisertib, ornidazole, napabucasin, lenalidomide, daniquidone, indoximod, Copyright: © 2020 by the authors. Li- and salicylamide, could be vital for the treatment of COVID-19. However, extensive in vivo and censee MDPI, Basel, Switzerland. This in vitro studies are required to evaluate the mentioned drug’s activity. article is an open access article distributed under the terms and conditions of the Keywords: COVID-19; antiviral agents; drug repurposing; molecular docking; molecular dynamics; Creative Commons Attribution (CC BY) E-pharmacophore hypothesis; virtual screening license (https://creativecommons.org/ licenses/by/4.0/). Biology 2021, 10, 2. https://dx.doi.org/10.3390/biology10010002 https://www.mdpi.com/journal/biology Biology 2021, 10, 2 2 of 14 1. Introduction Novel coronavirus disease (COVID-19) has become a threatening illness globally and was declared as a pandemic by WHO (World Health Organization). COVID-19 started spreading from the Wuhan seafood market in China since December 2019 [1]. As of the writing of this paper, 1,151,622 persons have died so far in COVID-19 and confirmed cases of persons with COVID-19 are 42,662,304 [2]. Coronavirus (CoVs) are the family of Coronaviridae, which is single-stranded en- veloped positive RNA virus subdivided into alpha (α), beta (β), gamma (γ), and delta (δ). Among them, the coronavirus β (β-CoV) group is divided into severe acute respiratory syn- drome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2), and middle east respiratory syndrome coronavirus (MERS-CoV) [3]. These three types of virus are highly fatal and responsible for respiratory, liver, gastrointestinal, and cen- tral nervous system damage in humans and animals [4]. In case of respiratory disease, it can lead to severe pneumonia with several symptoms, including fever, dry cough, vomiting, fatigue, diarrhea, and shortness of breath [5,6]. SARS-CoV-2 responsible for COVID-19 is extremely infectious and more pathogenic than SARS-CoV and MERS-CoV, which can transmit from human to human and cause fatal illness [5]. As there are no potential drugs or vaccines against coronavirus until now, emergency investigations are required to establish effective treatment. Several groups of drugs are being investigated against COVID-19, which includes drugs, namely hydroxy- chloroquine, chloroquine, lopinavir, ritonavir, remdesivir, etc., used for the treatment of SARS-CoV, MERS-CoV, and other viruses. However, there is an emergency requirement to establish novel, selective, and potential inhibitors against COVID-19 for the effective treatment [7]. In this short period of time, repurposing of drugs is a significant way to find out potential inhibitors against COVID-19. During repurposing, virtual screening, pharmacophore modeling, and other computational methods are extensively used [8]. The main protease (Mpro/3CLpro) is an attractive drug target due to its vital function that regulates polyproteins translated from the viral RNA [9]. The aim of our study was to focus on the SARS-CoV-2 main protease as a potential drug target to screen drugs for repurposing against COVID-19. The viral protein with a bound inhibitor was subjected to E-pharmacophore and molecular docking-based virtual screening to determine promising inhibitors of novel coronavirus. In addition, potential drugs were investigated through MM/GBSA and binding interaction for further analysis. 2. Materials and Methods 2.1. Sequence Comparison The crystal structures of SARS-CoV-2 Mpro (PDB ID: 5R7Y) [10], SARS-CoV Mpro (PDB ID: 2C3S) [11], and MERS-CoV Mpro (PDB ID: 5C3N) [12] were obtained from protein data bank. Afterwards, the protein structures were transferred into discovery studio soft- ware in order to align and explore their structural sequence for comparison purposes [13]. Accordingly, SARS-CoV-2 main protease (PDB ID: 5R7Y) in complex with Z45617795 at a resolution of 1.65 Å was used for further investigation. 2.2. Protein Preparation Pre-processing of the structure of the COVID-19 main protease in complex with Z45617795 was carried out through transformation of selenomethionines into methion- ines, removal of water molecules, and addition of missing hydrogen atoms followed by minimization of the structure utilizing the OPLS3 force field [14]. All these steps were performed utilizing the protein preparation wizard of Schrödinger Maestro (Protein Prepa- ration Wizard; Epik, Schrödinger, LLC, New York, NY, USA; v.11.1) [15]. In a similar manner, COVID-19 main protease in complex with inhibitor N3 at 1.7 angstrom (PDB ID: 7 BQY) was prepared. Biology 2021, 10, 2 3 of 14 2.3. Generation of E-Pharmacophore Hypothesis Previously prepared protein was subjected to E-pharmacophore hypothesis establish- ment using phase module of Schrodinger suit (Phase, Schrödinger, LLC, New York, NY, USA; v.11.1) to generate the pharmacophoric features [16]. Different features, namely aro- matic ring (R), hydrogen bond acceptor (A), hydrogen bond donor (D), positive ion (P), negative ion (N), and hydrophobicity (H), were mapped to form the protein-ligand com- plex. 2.4. Virtual Screening using E-Pharmacophore Hypothesis The molecular structure of 8820 drugs from the DrugBank database were screened for promising candidates against SARS-CoV-2 main protease (Mpro) enzyme utilizing the pharmacophoric features from the established E-pharmacophore hypothesis [17]. E- pharmacophore-based screening was carried out by the phase ligand screening module of Schrodinger Suit [16].
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