key: cord-0851622-2hxzd1or
authors: Rahman, Mohammad Rejaur; Banik, Anik; Chowdhury, Ishtiak Malique; Sajib, Emran Hossain; Sarkar, Sanchita
title: “Identification of potential antivirals against SARS-CoV-2 using virtual screening method”
date: 2021-02-10
journal: Inform Med Unlocked
DOI: 10.1016/j.imu.2021.100531
sha: 1967b1a91b48affedd081ffc113934bf667a3942
doc_id: 851622
cord_uid: 2hxzd1or

SARS-CoV-2 has triggered a major epidemic among people around the world, and it is the newest in the sequence to become prevalent among other infectious diseases. The drug repurposing concept has been utilized effectively for numerous viral infections. Considering the situation and the urgency, the idea of drug repurposing for coronavirus infection (COVID-19) is also being studied. The molecular docking method was used for the screening of 29 antiviral drugs against primary protease proteins (MPP) of SARS-CoV-2, spike ecto-domain, spike receptor binding domain, Nsp9 RNA binding protein, and HR2 domain. Among these drugs, in terms of least binding energy, Indinavir, Sorivudine, Cidofovir, and Darunavir showed minimum docking scores with all the key proteins. For ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) analysis, the ADMET properties of the top 4 drug candidates were retrieved through literature study. This analysis revealed that these drug candidates are well metabolized, distributed, and bioavailable, but have some undesirable effects. Furthermore, some approved structural analogues, such as Telbivudine, Tenofovir, Amprenavir, Fosamprenavir, etc., were predicted as similar drugs which may also be used for treating viral infections. We highly recommend these drug candidates as potential fighters against the deadly SARS-CoV-2 virus, and suggest in vivo trials for experimental validation of our findings.

The Health Authority of China notified the World Health Organization (WHO) about severe pneumonia cases in Wuhan City of Hubei Province in central China on December 31, 2019 [1, 2] . Later, this emerging infectious disease was named novel coronavirus disease 2019 , and the causative agent was determined to be severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) [3] . A well-known scientist in the field of SARS, Dr. Zhengli Shi, suggested the bats as the origin of SARS-CoV-2 [4] , and other researchers in China also narrated that Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) like coronaviruses are likely to originate from bats in China [5, 6] . This SARS-CoV-2 is an envelope and positive-sense single-stranded RNA (+ssRNA) virus [7] . It belongs to the genus SARS-CoV-2, such as proteins required for viral replication or proteins that bind to the human receptors (ACE2: angiotensin-converting enzyme 2). Our present research focused on virtual screening of a variety of antiviral drugs approved by the Food and Drug Administration (FDA).

These drugs were screened against the promising targets, namely SARS-CoV-2 main protease (Mpro, PDB ID-6W63), which is very necessary for viral replication, and spike receptor binding domain (PDB ID-6MOJ), which is needed to bind to human receptor ACE2. Other drug targets include Nsp9 (Nonstructural protein-9) RNA binding protein, Spike Ectodomain and HR2 domain, which are involved in viral replication, receptor binding and fusion, and viral fusion with cell membrane, respectively. The studied FDA approved antiviral drugs such as Sorivudine, 

The Molecular dynamics of the complexes were studied in water explicit model for 4ns using LARMD server, and from which RMSD and RMSF values were determined [51].

A typical drug candidate should have proper properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET) along with sufficient efficacy against the therapeutic targets [52] . As the studied drugs are approved, the ADMET properties of these drugs were retrieved from the literature study, and then were analyzed.

Screening of the top drugs was performed to find similar potential drugs that could be used for there is absence of hepatotoxicity. Lastly, Sorivudine shows a lethal effect when coadministrated with 5-fluorouracil anti-cancer drugs ( Table 2) . These similarity findings indicate the efficacy of these related drugs against SARS-CoV-2, and suggest further experimental studies. binding with single stranded RNA. SARS-Cov-2, moreover, has a surface structural spike glycoprotein (S) which plays a crucial role in association with the cell receptor, and subsequent viral passage into the cell. The S protein is composed of two subunits, the S1 (receptor-binding) and the S2 (membrane fusion) domain [40] . Interaction between the HR1 and HR2 domains in the membrane fusion subunit is enabled via the attachment of the receptor-binding subunit to the receptor, and forms a six-helix bundle. This conformational shift results in a close apposition of the fusion peptide that leads to virus-cell membrane fusion [86] . Hence, spike protein binds to human ACE2 and CLEC4M/DC-SIGNR receptors, and the internalization of the virus into the host cell endosomes results in the conformational changes in the S glycoprotein [87] . Therefore, all these macromolecules are the potential targets for repurposing study.

Based on global energy, four drugs among our studied 29 drugs showed comparatively well binding affinity against our targeted macromolecules. Indinavir had highest binding affinity with region) are characterized by positively charged, glycine rich β-loops, which were proposed to be involved in RNA binding [89] . Moreover, we targeted three distinct domains of SARS-CoV-2 spike protein, all of which play essential roles in the mechanism of viral entry into the host cell [90] . To unravel the drug surface hotspots of the studied SARS-CoV-2 proteins, the structural conformation of the docked complexes was analyzed. The pattern of ligand binding residues interacting with their respective positions had been studied (Table 1) [94] . The molecular dynamics study showed that the complexes were resistant to deform with higher eigen value, and were fluctuated almost regularly in RMSD and RMSF plots ( Figure 4 ). ADMET data is crucial in drug development projects whether it is determined by in vitro, in vivo, or computational approaches because many drug development projects previously failed during clinical trials due to poor ADMET data [95] . The ADMET analysis of these drugs showed that these are well metabolized, distributed, and bioavailable, but have some undesirable effects. Most of the target class for the top drug candidates fall into the enzyme categories such as electrochemical transporter, protease, transferase, Family A G protein-coupled receptor, etc., (Table 3) .

Ligand based drug similarity analysis identified three structural analogs of Indinavir where two (Quinapril, Sirolimus) are approved, and another one (L-756,423) is in the experimental stage.

Quinapril, an ACE (angiotensin converting enzyme) inhibitor, is used for treating heart failure and hypertension [96] . As we know that, SARS-CoV-2 enters the host cell by interacting with ACE-2 receptor, thus this analog could be a drug of choice to treat Covid-19. Besides, drug similarity analysis revealed two (Telbivudine & Idoxuridine) approved analogs for Sorivudine, and both of them act by incorporating into viral DNA in place of thymidine resulting in the termination of replication process. Telbivudine and Idoxuridine are used to treat hepatitis B virus (HBV) and Herpes simplex virus, respectively [97, 98] . Amprenavir and Fosamprenavir are two approved analogs of Darunavir, and both of them are protease inhibitors. These analogs prevent the processing of viral Gag and Gag-Pol polyprotein, and produce noninfectious and immature viral particles that is are harmless to host cell [99, 100] . The findings suggest that all these compounds may be used against SARS-CoV-2 as potential drug candidates

The results indicate that it may be possible for Indinavir, Sorivudine, Cidofovir, and Darunavir to fight SARS-CoV-2 infection. Furthermore, several biologically active structural analogs from DrugBank, i.e. Telbivudine, Tenofovir, Fosamprenavir, Tenofovir, etc., may also be successful against the viral pathogen. We strongly recommend these drug candidates as potential warriors J o u r n a l P r e -p r o o f because of promising results, and refer in vivo trials for experimental confirmation of our findings.

The authors declared that they have no conflicts of interest in this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. [77] P.Willett, Similarity-based virtual screening using 2D fingerprints, Drug Discovery J o u r n a l P r e -p r o o f 

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Department of Molecular Biology and Genetic Engineering, Sylhet Agricultural University for their technical support.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Please check the following as appropriate:All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript