key: cord-0056792-keapl1l3
authors: Anand, Jigisha; Ghildiyal, Tanmay; Madhwal, Aakanksha; Bhatt, Rishabh; Verma, Devvret; Rai, Nishant
title: Computational guided approach for drug repurposing against SARS-CoV-2
date: 2021-03-02
journal: nan
DOI: 10.2217/fvl-2020-0403
sha: c777188c9d611fc3feb3dae30a3e57962f446907
doc_id: 56792
cord_uid: keapl1l3

Background: In the current SARS-CoV-2 outbreak, drug repositioning emerges as a promising approach to develop efficient therapeutics in comparison to de novo drug development. The present investigation screened 130 US FDA-approved drugs including hypertension, cardiovascular diseases, respiratory tract infections (RTI), antibiotics and antiviral drugs for their inhibitory potential against SARS-CoV-2. Materials & methods: The molecular drug targets against SARS-CoV-2 proteins were determined by the iGEMDOCK computational docking tool. The protein homology models were generated through SWISS Model workspace. The pharmacokinetics of all the ligands was determined by ADMET analysis. Results: The study identified 15 potent drugs exhibiting significant inhibitory potential against SARS-CoV-2. Conclusion: Our investigation has identified possible repurposed drug candidates to improve the current modus operandi of the treatment given to COVID-19 patients.

The 3D structure of the structural and nonstructural proteins of SARS-CoV-2 were retrieved in protein data bank (PDB) format (.pdb) using the PHYRE program (Protein Homology/analogy Recognition Engine). The amino acid sequences were derived from the RCSB PDB in a FASTA format (www.rcsb.org/). The physicochemical and functional characterization of proteins was determined using Expasy's Prot-param server [29] . The 3D-protein homology models were generated from the SWISS MODEL workspace [30, 31] . The protein homology models were validated with a Ramachandran plot using the SWISS MODEL workspace. The stereochemical quality of the protein structures was assessed by PROCHECK to evaluate the presence of conserved sequences and related geometry of proteins [32] .

The ligand molecules used in the study belong to different classes of medicinal drugs including: antiviral drugs (type-I); anticoagulants, antihypertensive drugs, and drugs against cardiovascular disease and RTIs (type-II); and other miscellaneous antimicrobial agents (type-III). The code of SMILES for all the aforementioned test molecules was procured from the online chemical database PubChem (https://pubchem.ncbi.nlm.nih.gov/) (Tables 1A, 1B & 1C) . The 3D structures of the test molecules were then obtained by converting the SMILES code (.smiles format) into PDB (.pdb) format using chemical interconversion software Open Babel (v 2.3.1). The Drug Likeness reports of all the test molecules were prepared by submitting individual SMILES code for each drug to SwissADME -an omic tool aimed at understanding physicochemical description, pharmacokinetics and drug-like properties of small molecules [33, 34] . The toxicity and LD 50 of test compounds were analyzed using the admetSAR 2.0 version.

The binding efficacy of test molecules with the virulent proteins of SARS-CoV-2 was determined by performing docking analysis using iGEMDOCK software (v 2.1), which provides a graphical environment for recognizing pharmacological interactions and virtual screening. The iGEMDOCK generates protein-compound interaction profiles of electrostatic, hydrogen bonding and Van der Waals interactions and infers the pharmacological interactions as well as clusters the screening compounds for the postscreening analysis [35] . On the grounds of evaluated binding energies, it was presumed that how far the drug binds to the target macromolecule. For our study, we used standard docking with a population size of 200, 70 generations and two solutions.

The 3D structures of the SARS-CoV-2 proteins were generated from the SWISS MODEL workspace. Physicochemical and functional characterization of the SARS-CoV-2 structural and nonstructural proteins was analyzed using Expasy's Prot-param server ( Table 2 ). The structural templates for protein homology modeling were determined using the SWISS MODEL workspace. The template 6zhg.1.C. with 99.68% of sequence identity was observed for homology modeling of spike glycoproteins, while other protein models showed a 100% sequence identity with their respective templates ( Table 3) .

The Ramachandran plot depicted structural stability and showed confirmation of residues in the favorable region (Supplementary Figure 1 & Supplementary Table 3) . A Ramachandran phi-psi plot for all the seven proteins revealed 88.06-99.40% residues in the allowed region (light grey), and only 0.17-2.06% lay in the disallowed region (white). The above analysis of the predicted structure provides supporting evidence that suggests the predicted 3D structures of SARS-CoV-2 are significant for the docking study. The protein models showed local similarity to the crystal structures of target templates (Supplementary Figure 2) . The Q-mean value of protein models was reliable as depicted in the protein homology analysis (Supplementary Figure 3) .

The molecular docking using iGEMDOCK generated the binding energies of interaction between ligands and the structural PDB proteins of SARS-CoV-2 (Tables 4A, 4B & 4C) . The inhibitory potential of all the drugs was assessed based on the binding energy of their interaction with respective proteins (Figure 2A , B, C & D). The favorable docking sites for the interaction between ligands and SARS-CoV-2 proteins were depicted by AADS (Supplementary Table 1 ).

ADMET analysis ADMET parameters, namely 'absorption', 'distribution', 'metabolism' and 'excretion', pharmacokinetic properties, and the drug disposition within an organism were determined using Swiss ADME. The LD 50 dose of all the compounds was estimated by the admetSAR 2.0 version, which is a useful tool for in silico screening of ADMET profiles of drug candidates and environmental chemicals.

The ADMET analysis showed moderate to high solubility and gastrointestinal (GI) absorption of antiviral drugs, while baloxavir marboxil, danoprevir and sofosbuvir were found to be soluble but exhibit low GI absorption. Out of 58 drugs studied in the type-II category, fosinopril, telmisartan, amiodarone and azithromycin showed poor solubility and low GI absorption. However, their docking analysis revealed favorable molecular interaction with main protease and nsp10 protein (Supplementary Tables 2A, 2B & 2C) . Among the type-III category of drugs, fidaxomycin, micafungin, virginiamycin, tunicamycin, amphotericin B and caspofungin depicted high binding affinity with SARS-CoV-2 main protease, N and E proteins, their ADMET analysis predicted the moderate solubility and low GI absorption. The lipophilicity of the investigated drugs was indicated between -9.31 and +9.3, except for butenafine hydrochloride (Log p = 0). An in silico drug likeliness analysis showed that most of the investigated drugs showed an agreement to the Lipinski, Ghose, Veber, Egan and Muegge rules (Supplementary Tables 2A, 2B & 2C) .

The study predicted the bioavailability of drugs based on the ADMET score, which was evaluated between 0.11 and 0.56. The admetSAR 2.0 server was used to predict the rat acute toxicity or LD 50 value in mol/kg body weight. The study indicated that all the drugs tested against SARS-CoV-2 proteins have LD 50 values ranged between 0.17 and 4.42 mol/kg (Supplementary Tables 3A, 3B & 3C) .

SARS-CoV-2 has emerged as the causal virus for the ongoing COVID-19 pandemic that has spread worldwide. Currently, the cure for COVID-19 is still under trial or observation and multiple researches are ongoing globally to develop a promising vaccine or an antiviral drug. Several drugs like remedesvir and hydroxychloroquine have shown promising results in the treatment of COVID-19 and many more drugs are still under clinical trials. In the current scenario where a completely effective and specific vaccine or drug is still lacking, repurposed drugs could open a new gateway in developing an effective alternative to combat SARS-CoV-2 infection [36] .

The SARS-CoV-2 protease is an appealing and important drug target due to its potential involvement in the invasion and replication of the virus. In our study, 15 antiviral drugs with recognized inhibitory potential against different viruses were investigated for their inhibitory activity against SARS-CoV-2. Remdesivir, chloroquine and hydroxychloroquine have been identified as strong inhibitors of the main protease. These drugs are recognized by the WHO among the four potent means of therapeutics against SARS-CoV-2 during the current COVID-19 pandemic [37] . It has been proposed that chloroquine and hydroxychloroquine could alter the endosomal pH and glycosylations of ACE-2 receptors in the host, which blocks binding of SARS-CoV-2 with the altered ACE-2.

The in silico, in vitro and human trials, have proposed the immunomodulatory effect of chloroquine and its derivative hydroxychloroquine in critically ill SARS-CoV-2 infected patients and have indicated their promising role as effective antiviral drugs for the treatment of COVID-19 infections [38, 39] . Apart from the aforementioned antiviral drugs, baloxavir marboxil, danoprevir, darunavir and sofosbuvir showed significant interaction with the main protease with the least binding energies, which are -384.06, -489.67, -364.859 and -345.646 kcal/mol, respectively.

Recent in vitro studies have demonstrated the role of darunavir in inhibition of viral entry and replication of SARS-CoV-2 via targeting viral protease [26] . However clinical trials for the safety and efficacy of darunavir are still undergoing [40] .

The previous in silico study has identified RNA-dependent RNA polymerase as the target of sofosbuvir, which is a known antiviral drug used against RNA viruses. In clinical trials, the susceptibility of SARS-CoV-2 to sofosbuvir has been also explored [41] . The clinical efficacy of anti-influenza drugs like baloxavir marboxil and favipiravir was tested in vitro against SARS-CoV-2 and has been demonstrated to exhibit inhibitory potential against RNA synthesis [42] .

Therefore, based on the previous in silico, in vitro and clinical studies as well as the present molecular docking analysis, it can be suggested that besides remdesivir, chloroquine and hydroxychloroquine; other antivirals like baloxavir marboxil, danoprevir and sofosbuvir represent an alternative and a novel drug candidate against SARS-CoV-2. However, drug likeliness report in our investigation also depicted that danoprevir, darunavir, favipiravir and lopinavir are toxic as they have violated three to four rules from Lipinski's rule of five. The toxicity level of danoprevir could restrict its application as a potent candidate for antiviral therapy; however, the dose regime of the drug is one of the highlighted parameters which is important to be analyzed for the drug toxicity [43] .

SARS-CoV-2 enters the host cell by binding to its surface receptors called ACE-2, which are expressed by alveolar epithelial cells [22] . ACE-2 is closely related to ACE, a target of hypertensive drugs. ACE converts angiotensin-I to angiotensin-II, which is known for the narrowing of blood vessels and an increase in blood pressure. Angiotensin-II binds to the target ACE-2 receptors, releasing vasodilatation (angiotensin 1-7) . Recent studies have demonstrated the downregulation of ACE-2 in response to viral attachment and deteriorating the health conditions of patients with comorbid conditions like hypertension and RTIs [43, 44] .

The antihypertensive drugs block angiotensin-I-mediated vasoconstriction and enhance the expression of ACE-2 on the cell surface. This mechanism might impart protection to the lungs and prevents the patients from the high risk associated with SARS-CoV-2 [45, 46] . We have investigated the interaction of 58 drugs under the type-II category including ACE-2 inhibitors, ARBs, αand β-blockers, anticoagulants, and RTI drugs. We identified seven drugs including fosinopril, moexipril, quinapril, telmisartan, azilsartan, verapamil and doxazosin to posses significant interaction with the main protease of SARS-CoV-2. The ACE-2 inhibitors like fosinopril, moexipril and quinapril demonstrated the most significant docking poses with the main protease and N protein with the lowest binding energy. Furthermore, investigation of docking analysis of ARBs and molecular targets of SARS-CoV-2 showed effective binding affinity of telmisartan, azilsartan, verapamil and doxazosin toward main protease. Recent studies have also depicted the role of antihypertensives such as losartan, olmesartan and telmisartan as antiviral agents against SARS-CoV-2 infection while the clinical trial of telmisartan for COVID-19 therapy has recently started [47, 48] . Henceforth, the role of these antihypertensive drugs as promising anti-SARS-CoV-2 drugs cannot be ruled out and could be a subject of future research for assessing their application as repurposed drugs in COVID-19 infection.

The structural and nonstructural viral proteins have the most gruesome role in its infection cycle. Considering their importance in viral attachment, invasion, replication and pathogenicity, we have studied the possible effect of antimicrobial agents targeting the protein or their synthesis. In our computational study, we investigated the binding affinity of 56 such miscellaneous drugs that interacted effectively with the binding site of SARS-CoV-2 proteins. There are previous experimental proofs that have highlighted the application and potential of various antibacterial and antifungal agents targeting intracellular processes like replication, protein synthesis, and cell cycle in viruses like vesicular stomatitis virus, herpes simplex virus types 1, Sindbis virus, influenza virus, vaccinia virus and HIV-1 [49] [50] [51] [52] .

Antibacterial drugs such as azithromycin, doxycycline, clarithromycin, rifamycin and augmentin (a combination of amoxicillin and clavulanate) are specifically used for the treatment of throat, chest infection and pneumonia. In our study, these antibiotics were identified to exhibit significant binding efficacy at the target site of the main protease (nsp-5) and nsp10. The antiviral potential of several other antibacterial drugs like lymecycline, demeclocycline and eravacycline has been studied in silico and in vitro, which also indicated the possible application of antibiotics drugs against SARS-CoV-2 [53] . The possible mechanism of the antiviral effect of these antibiotics could lie in the immunopathology of SARS-CoV-2 that resulted in decreased expression of CD-147, which is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. The CD-147 glycoproteins are expressed by epithelial cells, macrophages and type II pneumocytes, and act as an upstream stimulator of matrix metalloproteinases and induce progression of cancer cells. Wang et al. have demonstrated CD-147 as an effective receptor SARS-CoV-2 S protein [53] . Antibiotics such as doxycycline and azithromycin have shown reduced expression of CD-147 on carcinoma cell lines, and therefore, these agents could prove to be a possible repurpose drug candidate for SARS-CoV-2 [54] .

The present study showed that virginiamycin, tunicamycin, quinipristin, fidaxomycin, digoxin and azithromycin exhibited stable interaction to the residues in the binding pockets of the main protease with the least binding energies. In a previous study, fidaxomicin has also shown effective antiviral efficacy against other viruses like the ZIKA virus and has depicted inhibition of RNA-dependent RNA polymerase and subsequent viral infection in vitro and in vivo [55] . Antifungal drugs like caspofungin, amphotericin B, ketoconazole and macfungin were found to elicit antiviral effect by showing significant binding affinity toward E and N proteins. In different studies conducted against enterovirus 71, the inhibitory potentials of antifungal drugs like micafungin and amphotericin B were mentioned against enterovirus 71 [50, 51] . The spike glycoprotein (S protein) plays an essential role in the wide host tropism of SARS-COV-2 and mediates its pathogenicity via binding to host cell surface receptors and enabling its entry into the host cell [40, 41] . Out of 130 drugs, two of the antibiotics namely virginiamycin (-428.28 kcal/mol) and amphotericin B (-301.254 kcal/mol) revealed strong interaction with S protein in the present molecular docking study. Therefore, it is a matter of future investigation to assess whether these antibiotics could prevent cleavage and activation of S1/S2 subunits of S protein and hence could inhibit viral attachment to the host cell receptor.

Mammalian metabolism and toxicity of all the proposed repurposed drugs were tested through ADMET analysis using SWISS-ADME server and admetSAR version 2.0. In terms of drug development; solubility, dissolution and permeability across the GI barrier are the prime focus since drug absorption is important before any associated medical effect can be induced. The solubility and the GI absorption are essential and rate-limiting steps for preformulation interpretations in drug development [56, 57] . The potency of any drug is also determined by its ability to reach the blood-brain barrier, which isolates brain tissues from the substances circulating in the blood vascular system. The present study indicated poor membrane permeation properties of all the tested 130 drugs across endothelial capillaries (blood-brain barrier) [58, 59] .

Permeability glycoprotein (Pgp) or CD243 is an ATP-dependent drug efflux pump extensively distributed and expressed as a receptor on intestinal epithelium that pumps toxins or drugs back into the intestinal lumen and liver [60, 61] . CYP450 (CYP3A4) is the main enzyme that catalyzes drug metabolism in the intestine and liver. The co-existence of CYP3A4 and Pgp at the same site synergistically reduces the bioavailability of the drug [62, 63] . There was no overlapping observed in CYP3A4 and Pgp suggesting the high bioavailability of the tested drugs.

The study unveils the lipophilic property of all 130 drugs and showed the lipophilic nature of 122 drugs with a positive value of Log P (Log p > 0), while drugs like foscarnet, adenosine-5 -[beta, gamma-methylene] triphosphate, augmentin, minoxidil, hydrochlorothiazide, losartan and fosinopril indicated their hydrophilic nature and higher affinity for the aqueous phase (negative value of Log P). The optimization of pharmacodynamic and pharmacokinetic characteristics of hits and leads in drug development is crucial and is highly dependent on the drug lipophilicity [64, 65] .

In the current study, out of 130 drugs that belong to the different class, 15 drugs were identified to be the significant inhibitors of SARS-CoV-2 proteins. The computational study of the target protein and drugs molecular interaction highlighted the potential of baloxavir marboxil, danoprevir, sofosbuvir, fosinopril, quinapril, telmisartan, atrovastatin, sulfamethoxazole, clarithromycin, micafungin, virginiamycin, tunicamycin, fidaxomycin, amphotericin B and caspofungin as a potent inhibitor of SARS-CoV-2 proteins, and therefore, these identified compounds could be explored for their role as future drug candidates against COVID-19.

The biochemical characterization, the pharmacokinetics of the aforementioned potent drugs and the computational analysis of their molecular interactions with SARS-CoV-2 proteins have provided preliminary breakthrough which could lead to exploring their avenues in repurposed drug development. It is pertinent that drug repurposing is an alternative way to curb pandemics like medical emergencies and thus their efficacy to combat SARS-CoV-2 related serious health complications should be explored.

Hence, the effectiveness of baloxavir marboxil, danoprevir, sofosbuvir, fosinopril, quinapril, telmisartan, atrovastatin, sulfamethoxazole, clarithromycin, micafungin, virginiamycin, tunicamycin, fidaxomycin, amphotericin B and caspofungin targeting the structural and nonstructural proteins indicates the possibilities of success of repurposing these drugs against SARS-COV-2. Further in vitro and in vivo studies of screened compounds alone and their varying combinations could provide an insight into the development and application of these compounds as potent anti-SARS-CoV-2 drugs.

The study attempted to highlight the inhibitory potential of drugs namely, baloxavir marboxil, danoprevir, sofosbuvir, fosinopril, quinapril, telmisartan, atrovastatin, sulfamethoxazole, clarithromycin, micafungin, virginiamycin, tunicamycin, fidaxomycin, amphotericin B and caspofungin, and thus, revealed their prospects in drug repurposing to combat SARS-CoV-2. The study might lead the way for clinicians, pharmaceutical experts to investigate and further validate these compounds as potent novel and efficacious antiviral therapy against COVID-19 infection. 10 .2217/fvl-2020-0403 Future Virol. (Epub ahead of print) future science group

• The study investigated the inhibitory potential and molecular targets of 130 compounds categorized into three types: antivirals (type-I); drugs used in cardiovascular diseases, respiratory tract infection and hypertension (type-II); and antibacterial/antifungal drugs (type-III) against SARS-CoV-2 through computational docking tools. • Out of 130 compounds, 15 drugs were identified to be significant inhibitors of SARS-CoV-2 and showed a favorable binding affinity with viral S protein, N protein, E-protein, nsp-5, nsp10, nsp-16. • The identified potent drug candidates such as baloxavir marboxil, danoprevir, sofosbuvir, fosinopril, quinapril, telmisartan, atrovastatin, sulfamethoxazole, clarithromycin, micafungin, virginiamycin, tunicamycin, fidaxomycin, amphotericin B and caspofungin showed promising pharmacokinetic properties and low acute toxicity profile. • The investigation might lead the way for authenticating the inhibitory potential of these screened compounds by in vitro and in vivo studies, and further exploring their activity and applications as an individual compound or in varying combinations against SARS-CoV-2.

To view the supplementary data that accompany this paper please visit the journal website at:

www.futuremedicine.com/doi/suppl/10.2217/fvl-2020-0403

All the authors equally contributed in the study.

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We are highly thankful to the Department of Biotechnology and Life Sciences, Graphic Era (Deemed to be University) for giving us the opportunity and providing all the technical facility to execute this extensive study.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.