Virtual Screening of Phytochemical Compounds as Potential Inhibitors against SARS-CoV-2 Infection

doi:10.21203/rs.3.rs-77456/v1

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Virtual Screening of Phytochemical Compounds as Potential Inhibitors against SARS-CoV-2 Infection

https://doi.org/10.21203/rs.3.rs-77456/v1

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Background: The present pandemic situation due to coronavirus has led to the search for newer prevention, diagnostic and treatment methods. The onset of the corona infection in a human results in acute respiratory illness followed by death if not diagnosed and treated with suitable anti-retroviral drugs. With the unavailability of the targeted drug treatment, several repurposed drugs are being used for treatment, However, the side-eﬀects of the drugs urges us to move to a search for newer synthetic or phytochemical based drugs. The present study investigates the use of various phytochemicals virtually screened from various plant sources in Western Ghats, India and subsequently molecular docking studies were performed to identify the eﬃcacy of the drug in retroviral infection particularly coronavirus infection.

Results: Out of 57 phytochemical screened initially based on the structural and physicochemical properties, 39 were eﬀectively used for the docking analysis. Finally 5 lead compound with highest hydrophobic interaction and number of H-bonds were screened. Results from the interaction analysis suggests, Piperolactam A to be pocketed well with good hydrophobic interaction with the residues in the binding region R1. ADME and toxicity proﬁling also reveals Piperolactam A with higher LogS vlaues indicating higher permeation and hydrophilicity. Toxicity proﬁling suggests that the 5 screened compounds to be relatively safe.

Conclusion: The insilico methods used in this study suggests that the compound Piperolactum A to be the most eﬀective inhibitor of S-protein from binding to the GRP78 receptor. By blocking the binding of the S-protein to the CS-GRP78 cell surface receptor, they can inhibit the binding of the virus to the host.

Structural Biology

Insilico Drug Design

Virtual Screening

Retroviral Infection

COVID-19, an infectious disease caused by Severe Acute Respiratory Syndrome Virus (SARS-CoV-2) has become an unexpected threat to the human population. With the exponential raising of the infection followed increasing mortality rate day by day; the World Health Organization ((WHO)) has reported active cases 14,348,858 and death of 603,691 humans on July 20^th^, 2020 [1]. The threat has forced a major responsibility to scientiﬁc society in the search for new diagnosis methods, treatment and preventive solutions. Existing repurposed drugs are been neglected by the medical community due to associated side eﬀects [2].

CoV belongs to the family Coronaviridaewith a large RNA genome of 30 kb, positive-sensed and non-segmented [3]. The virion structure contains four parts of protein which are Spike proteins (S-proteins), Membrane proteins (M-proteins), Envelope proteins (E-proteins) and Nucleocapsid proteins (N-proteins). Of these S-proteins play a major role in transfer of virion particles from the virus to the host cells using ACE2 [4]. Although various literature have highlighted the importance of other protein; the S-protein is currently well studied and has been considered to be as a potent drug target [5]. The S-protein exhibit in homo-trimeric state with N-terminal glycosylation in which the S-polypeptide chain cleaved into two subunit S1 and S2 [3]. The S1 subunit with the larger receptor binding domain and the S2 subunit which induces the membrane fusion polypeptides forming the six helix bundle which results in complete fusion and insertion of viral genome to the host cell cytosol [6]. Hence, structural analysis on the S-protein could reveal possible mechanisms by which the viral replication could be terminated/controlled [7].

Till date many studies are involved in targeting ACE2 receptor (Angiotensin Converting Enzyme-2), an amino peptidase which found to act as a cellular gateway for the entry of viral RNA into the cells using the S-proteins present in the surface of the virus [5, 8]. But, ACE2 receptor is not only the gateway present on cell membrane to carry this virion into the cells, there are other cellular surface proteins which could also take this role. One such protein is Glucose Regulated Protein 78 (GRP78) reside in lumen of Endoplasmic Reticulum (ER), a heat shock protein with a molecular weight of 78 kDa and a molecular chaperone present in all eukaryotic cells. The major role of GRP78 is protein folding, unfolding and resisting aggregation of proteins in cytosol [9]. The ER-protein when overexpressed escape the KDEL motif receptors which responsible for retention in ER due to its saturation or down regulation and get translocated in the cell membrane and act as Cell Surface GRP78 receptor (CS-GRP78 receptor) which pose the potential threat to our system for viral entry. Hypoxia, glucose starvation and tumor causes ER stress which thus upregulate the GRP78 genes and result in over production of GRP78 [10]. Malfolded protein accumulation also results in overexpression of this protein mostly reported in neurodegenerative disorders and conditions like Alzheimer, Parkinson’s disease and prion protein disease [11].

CS-GRP78 acts as a multifunctional receptor and binds plenty of proteins and other compounds and activates several pathways which have negative impact on the cells like apoptosis [12]. Several studies reveal that this protein has been responsible for many types of viral entry. In entry of CoxsackieVirus A9 CS-GRP78 involved as the co-receptor along with MHC Class 1 molecule one cell surface [13]. GRP78 studies reported an important host cell factor in the entry of Japanese Encephalitis Virus into the host cells [14]. Studies report that along with Dipeptidyl-peptidase 4 (DPP4), CS-GRP78 involved in the entry of MERS-CoV and reported that introduction of MERS-CoV into cells upregulate the GRP78 genes led to overproduction of GRP78 which both helps in viral entry as well as in virus development [15]. Conditions in which the primary receptor expression in host is low CS-GRP78 act as the main alternate door for the viral entry. Thus inhibiting or reducing CS-GRP78 mediated entry of SARS-CoV-2 is essentially equivalent to inhibiting the ACE2 mediated receptor entry [16]. Protein-protein docking studies established the possible binding site where these two proteins could form complex with good HADDOCK Score, PRODIGY Binding aﬃnity, H-bonds and hydrophobic interaction. It would be a good approach, if we could block the region of S-protein which is responsible for binding to the CS-GRP78 receptor.

Considering the pandemic situation, several health organization and nations in the aim of developing antiviral agents are repurposing drugs like Lopinavir (HIV), Hydroxychloroquinone (Malaria) against COVID [17, 18]. In general, repurposed pose variable target mechanisms and lack eﬀectiveness for coronovirus strain. On the other hand, antiviral drugs also exhibit adverse side eﬀects, which directly and indirectly aﬀect human health [19]. To overcome this shortfall, the development of plant-based drugs and treatment strategies with minimal side-eﬀects are expected [20]. Potentially phytochemicals, which serves as an inﬁnite resource for drug development and novel pharmacophore may be beneﬁted as a therapeutic agent against corona viruses. Their therapeutic applications against diverse viruses can be explained by various antiviral mechanisms such as inhibition of replication process [21], blocking the binding of virus to the host etc., [22].

Ancient Indian traditional techniques used several plant parts to treat various infections and disease conditions [23]. Plant parts used in the treatment was experimentally proven to pose eﬀective medicinal properties, further studies on their crude extract and compounds extracted from the plant proved that the extracts are contained with secondary metabolites like alkaloids, ﬂavonoids, phenols, chalcones etc and were termed as phytochemicals. A large number of phytochemicals pose antimicrobial, antiviral and antioxidant properties [24]. These plant parts which were used to treat the disease or infection were later experimentally proven for their medicinal properties [25]. Several literature studies and promising diverse biological assays reveal that a large amount of phytochemicals can be utilized as an eﬀective treatment for retroviral infections. Recently, phytochemicals are used as an inhibitory material for viral infection including HIV, inﬂuenza, common cold etc., [26, 27].

In this study, an attempt has been made to virtually screen potential phytochemicals with high eﬀectiveness particularly from plants originated from Western Ghats, INDIA. Intensive literature survey has been made prior to the screening of phytochemicals. Eﬀectiveness of the screened compounds were validated based on the in-silico docking technique by binding to the S-protein of SARS-CoV-2 and ranked based on the interaction analysis between the protein-receptor complex.

2.1 Computational Platform

All computational analysis were performed on Linux Mint 18 platform in a Dell T20 server on Intel Xeon Quad Core 3.2 Hz.

2.2 Receptor Preparation

The SARS-CoV-2 S-protein (PDB ID: 6X6P at 3.2 Å) with the spike glycoprotein was downloaded from RCSB Protein Bank (PDB). The protein is a trimeric viral fusion protein with subunits S1 and S2. S1 contains the Receptor Binding protein (RBD) responsible for host cell receptor binding and the S2 subunit facilitates the membrane fusion between the viral and host cell membranes. The viral protein contains 1274 amino acids and weigh 434.87 KDa. For the purpose of the study, we utilized only Chain A from the S-protein for docking analysis. Protein visualization and manipulation of the structures was done using UCSF Chimera [28].

2.3 Binding-site Preparation

The prediction of binding site was done with respect to the available literature [29] and then veriﬁed based on the presence of hydrophobic regions on the surface of the protein. For the purpose of the study, we utilized the same binding site between the S-protein and CS-GRP78, since our main aim is to block the binding of S-protein to the ER protien [29]. The hydrophobicity of the protein is calculated using GRAVY server [30]. The S-protein contains four hydrophobic regions in the Receptor Binding Domain (RBD) ranging from 318 to 510 aa of the S1 subunit. The binding energy values obtained from Protein Binding Energy Prediction (PRODIGY) [29].

2.4 Screening for Phytochemicals

Phytochemicals with antiviral, antimicrobial and antioxidant properties were screened based on the previous literature and were sorted, ﬁltered based on their geographical origin [31, 32, 33]. More than 100 compounds were initially screened. 3D and 2D structures were downloaded from PUBCHEM database [34] and drugbank.ca [35] in both SDF and Simpliﬁed Molecular Input Line Entry System (SMILES) format [36] for further screening procedures. In order to select the potential drug-like compounds, several ﬁlters were applied on the structures.

Initially, LIPINSKI rule of ﬁve (RO5) was applied to screen potential drug-like compounds [37]. Drug-like compounds screened from RO5 was further fed into SWISS-ADME server for screening based on the pharmacokinetics, drug-likeliness and medicinal chemistry friendliness of small molecules [38]. In addition, the physicochemical properties and the drugability of the selected compounds were also predicted with SWISS-ADME server. Hydrochloroquinone (HCQ) (PUBCHEM ID: 3652), a well known retro viral drug was used as a standard throughout the studies [39].

2.5 Multiple Ligand Docking

For the purpose of study, Autodock was employed for docking simulations [40]. Initially, water molecules and hetero atoms were removed from the structures [41]. Addition of gasteiger charges and H-bond was carried out prior to the docking protocol. A grid box of 25×22×19 (Å) was assigned on the surface of the receptor with respect to the identiﬁed active site. In this present study, multiple ligands have been screened against the receptor. Multiple ligand docking was carried out using PyRx in the Autodock environment [42]. The docked structures were analyzed for Root Mean Square Deviation (RMSD), lowest energy conformer and Hydrogen Bond (HB) interaction. 2D Protein-Ligand interaction proﬁle was obtained using Protein Plus Server [43, 44] and Protein Ligand Interaction Proﬁler [45].

2.6 Physicochemical Property of the Bound Ligand

To validate the bound ligand with the receptor, the physicochemical and pharmacokinetic properties of the drug is analyzed using SWISS-ADME server [38]. The toxicity proﬁle is analyzed using admetSAR 2.0 [46], which provides information on the ADMET properties. Screened compounds were subjected to Ghose ﬁlter [47] and Muegge Filter [48].

In the present study, 57 phytochemicals were initially screened based on their structural and physicochemical properties, later only 39 compounds were utilized for the docking analysis based on the various ﬁlter utilized during the course of the study. Binding sites was initially chosen based on the literature survey made on the target protein 6X6P. Potential binding sites were further selected based on the hydrophobic index obtained from GRAVY server. Results from GRAVY server indicates significant values for the four binding region R1-R4 as -0.24, -0.3, -0.28 and -0.08 respectively. Binding sites were also considered based on the their predicted binding energy by PRODIGY. Results from PRODIGY for the four binding regions R1 – R4 are -12.4 , -9.8, -10.1 and -14 kcal/mol respectively. Region 4 (R4) [-9.8 kcal/mol] and and Region 1 (R1) [-12.4 kcal/mol] of the S-protein pose a higher hydrophobicity. However, R1 was considered for the potential binding site.

Prior to the actual binding, the ligands are screened based on the RO5 and SWISS-ADME ﬁlters. Among the 39 ﬁnally screened compunds, only 5 compounds exhibited docking energy values above -8.9 to 8.3 kcal/mol for SARS-CoV-2 S-protein Region 1. Among them Tanshinone I exhibited an average docking score of -8.9 kcal/mol and Piperolactam A with a docking score of -8.3 kcal/mol ranked the strongest both in terms of binding energy and HB interaction. A list of all other ranked ligands based on the binding energy is listed in the Table 1. The standard ligand, HCQ resulted in a docking score of -4.7 kcal/mol and was used to compare other phytochemicals docked with the S-protein.

The HCQ-S-protein complex has two HB interaction with ARG355and TYR396 which contribute to the hydrophobic interactions. In comparison with HCQ, Tanshinone I has the highest binding aﬃnity of -8.9 kcal/mol compared to all other compounds and has one HB of distance 2.38 Å with the acceptor atom O2 of ASN343. Tanshinone I also formed a good hydrophibic interaction with the neighboring amino acids viz., PHE338, PHE342, VAL367, LEU368 and PHE374[Table. 1]. Whereas, the second lead compound Piperolactam A with binding aﬃnity -8.3 kcal/mol is found to form two HB interaction with the S-protein in which both bonds are from ASP364 to the compound with a distance of 1.99 Å and 2.05 Å.

Compounds with good ADME parameters are suitable for the drug discovery process. Analysis of the lipophilicity of the screened compounds showed positive values which indicates enhanced rate of adsorption [49] as described in supplementary material.

In this present study, although during the selection and validation of the predicted binding sites, both Region R1 and R4 resulted as a potential binding sites among the four predicted sites. Based on the hydrophobicity index, R4 is marked with higher index values, however, the site fails to show minimum interaction with the known receptor CS-GRP78 [10]. The binding affinity of R4 is -14 kcal/mol which is much lower than the R1 with -12.4 kcal/mol. Based on the binding affinity values, R1 is considered to be as potential binding site for the screened ligands. The binding site involves the residues of ASN343, ASP364, GLY339, ARG355and ARG466. Additional amino acids at the active site are PHE338, VAL367, LEU368, PHE342, PHE337and TYR396 [Fig.1].

With respect to screened ligands, the hydrophilicity factor (LogS) of Camptothecin (-3.49) and Piperolactam A (-3.87) showed higher LogS values (high permeation and hydrophilicity) than the other screened compounds [50]. Among the screened compound, Ellipticine (-5.05) showed a less LogS value indicating a poor permeation. Similarly, anabsinthin acts a good substrate for P-glycoprotein, which is highly susceptible to changes in pharmacokinetics by acting as either P-glycoprotein inducer or inhibitors [51]. Thus, anabsinthin could cross the Blood Brain Barrier (BBB) and it may render the compound functionally inactive [52]. Further, Anabsinthin could not satisfy Ghose rule [47] of druglikeness with three violations and Muegge rule [48] of druglikeness with one violation. Piperolactam A showed a good pharmacokinetics properties with good GI absorption, cross BBB, aﬀect only two cytochrome P450 enzymes compared to others and is also not a substrate for P-glycoprotein. The phytochemical compound Piperolactam A has synthetic accessibility of 2.02 which makes it at ease of synthesis of the compound inspite of an alert in the Brenk ﬁlter. Whereas Camptothecin was found with no violations but its synthetic accessibility is of higher value than that of Piperolactam A. Toxicity analysis is essential for a drug to know the potential hazard to be produced by it. The predicted toxicity proﬁle from our study reveals that all the compounds are relatively safe.

Results from the docking analysis suggests that the piperolactam A pocketed well with good hydrophobic interaction with residues PHE338, PHE342and VAL367as well [Fig. 2]. Based on the results, obtained, the study suggest use of Piperolactum A as a potential antiretroviral drug against SARS-CoV-2. Piperolactum, an aristolactam isolated from Piper betle Linnand its abundant availability in Western Ghats [53].

In this study, 5 phytochemical compounds with antiretroviral properties were screened against the receptor 6X6P. These compounds displayed appreciable pharmocokinetic and physicochemical properties. ADMET analyses of these compounds reveals that the compound Piperolactam A from Piperaceae family to be most eﬀective in the inhibition of S-protein from binding to the CS-GRP78 receptor.

ACE2 - Angiotensin Converting Enzyme-2; ER - Endoplasmic Reticulum; DPP4 - Dipeptidyl-peptidase 4; CS-GRP78- Cell Surface Glucose Receptor Protein 78; HIV - Human Immuno-deﬁciency Virus; PRODIGY - Protein Energy Binding Prediction; SMILES- Simpliﬁed Molecular Input Line Entry System; BBB - Blood Brain Barrier.

Labrague LJ, de Los Santos J. COVID-19 anxiety among frontline nurses: predictive role of organisational support, personal resilience and social support. Journal of nursing management. 2020.
Saini M, Parihar N, Soni SL, Sharma V. Drug Repurposing: An Overview. Asian Journal of Pharmaceutical Research and Development. 2020;8(4):194–212.
Astuti I, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020.
Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4(6):1011–1033.
Roshanravan N, Ghaﬀari S, Hedayati M. Angiotensin converting enzyme-2 as therapeutic target in COVID-19. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020.
Kalathiya U, Padariya M, Mayordomo M, Lisowska M, Nicholson J, Singh A, et al. Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site. Journal of Clinical Medicine. 2020;9(5):1473.
Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, et al. Drug targets for corona virus: A systematic review. Indian journal of pharmacology. 2020;52(1):56.
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine. 2020;46(4):586–590.
Ge R, Kao C. Cell Surface GRP78 as a Death Receptor and an Anticancer Drug Target. Cancers. 2019;11(11):1787.
Ibrahim IM, Abdelmalek DH, Elﬁky AA. GRP78: A cell’s response to stress. Life sciences. 2019;226:156–163.
Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35(4):373–381.
Schönthal AH. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientiﬁca. 2012;2012.
Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochemical Journal. 2011;434(2):181–188.
Nain M, Mukherjee S, Karmakar SP, Paton AW, Paton JC, Abdin M, et al. GRP78 is an important host factor for Japanese encephalitis virus entry and replication in mammalian cells. Journal of virology. 2017;91(6).
Chu H, Chan CM, Zhang X, Wang Y, Yuan S, Zhou J, et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. Journal of Biological Chemistry. 2018;293(30):11709–11726.
Ha DP, Van Krieken R, Carlos AJ, Lee AS. The stress-inducible molecular chaperone GRP78 as potential therapeutic target for coronavirus infection. Journal of Infection. 2020;.
Muralidharan N, Sakthivel R, Velmurugan D, Gromiha MM. Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 Protease against COVID-19. Journal of Biomolecular Structure and Dynamics. 2020;p. 1–6.
Tripathy S, Dassarma B, Roy S, Chabalala H, Matsabisa MG. A review on possible modes of actions of Chloroquine/Hydroxychloroquine: Repurposing against SAR-COV-2 (COVID 19) pandemic. International Journal of Antimicrobial Agents. 2020;p. 106028.
Ghildiyal R, Prakash V, Chaudhary V, Gupta V, Gabrani R. Phytochemicals as Antiviral Agents: Recent Updates. In: Plant-derived Bioactives. Springer; 2020. p. 279–295.
Biswas D, Nandy S, Mukherjee A, Pandey D, Dey A. Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review. South African Journal of Botany. 2020;129:272–282.
Kapoor R, Sharma B, Kanwar S. Antiviral phytochemicals: an overview. Biochem Physiol. 2017;6(2):7.
Subudhi BB, Chattopadhyay S, Mishra P, Kumar A. Current strategies for inhibition of chikungunya infection. Viruses. 2018;10(5):235.
Pandey M, Rastogi S, Rawat A. Indian traditional ayurvedic system of medicine and nutritional supplementation. Evidence-Based Complementary and Alternative Medicine. 2013;2013.
Naithani R, Mehta RG, Shukla D, Chandersekera SN, Moriarty RM. Antiviral activity of phytochemicals: a current perspective. In: Dietary Components and Immune Function. Springer; 2010. p. 421–468.
Petrovska BB. Historical review of medicinal plants usage. Pharmacognosy reviews. 2012;6(11):1.
Meher B, Purohit P, Dash JJ. Probing Phytochemicals As Prospective Antiviral Agents Against HIV-1 Protease Through Structure-Based Virtual Screening and Molecular Dynamics Simulations. Available at SSRN 3529932. 2020;.
Hota DK, Nayak D, Swain S, Bhattacharyay D. Capsicum Derived Phytochemicals against Shikimate Dehydrogenase of Haemophilus inﬂuenza causing Bronchitis. Journal of Pharmaceutical Research International. 2020;p. 128–131.
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimeraa visualization system for exploratory research and analysis. Journal of computational chemistry. 2004;25(13):1605–1612.
Ibrahim IM, Abdelmalek DH, Elshahat ME, Elﬁky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. Journal of Infection. 2020;.
ul Qamar MT, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. Journal of pharmaceutical analysis. 2020;.
Silambarasan R, Sureshkumar J, Krupa J, Amalraj S, Ayyanar M. Traditional herbal medicines practiced by the ethnic people in Sathyamangalam forests of Western Ghats, India. European Journal of Integrative Medicine. 2017;16:61–72.
Krishnan PN, Decruse S, Radha R. Conservation of medicinal plants of Western Ghats, India and its sustainable utilization through in vitro technology. In Vitro Cellular & Developmental Biology-Plant. 2011;47(1):110–122.
Venkatachalapathi A, Sangeeth T, Ali MA, Tamilselvi SS, Paulsamy S, Al-Hemaidc FM. Ethnomedicinal assessment of Irula tribes of Walayar valley of Southern Western Ghats, India. Saudi journal of biological sciences. 2018;25(4):760–775.
Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem 2019 update: improved access to chemical data. Nucleic acids research. 2019;47(D1):D1102–D1109.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic acids research. 2018;46(D1):D1074–D1082.
Weininger D. SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. Journal of chemical information and computer sciences. 1988;28(1):31–36.
Lipinski CA. Lead-and drug-like compounds: the rule-of-ﬁve revolution. Drug Discovery Today: Technologies. 2004;1(4):337–341.
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientiﬁc reports. 2017;7:42717.
Naghipour S, Ghodousi M, Rahsepar S, Elyasi S. Repurposing of well-known medications as antivirals: hydroxychloroquine and chloroquine; from HIV-1 infection to COVID-19. Expert Review of Anti-infective Therapy. 2020;.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor ﬂexibility. Journal of computational chemistry. 2009;30(16):2785–2791.
Huggins DJ, Tidor B. Systematic placement of structural water molecules for improved scoring of protein–ligand interactions. Protein Engineering, Design & Selection. 2011;24(10):777–789.
Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. In: Chemical biology. Springer; 2015. p. 243–250.
Fährrolfes R, Bietz S, Flachsenberg F, Meyder A, Nittinger E, Otto T, et al. Proteins Plus: a web portal for structure analysis of macromolecules. Nucleic acids research. 2017;45(W1):W337–W343.
Stierand K, Maaß PC, Rarey M. Molecular complexes at a glance: automated generation of two-dimensional complex diagrams. Bioinformatics. 2006;22(14):1710–1716.
Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein–ligand interaction proﬁler. Nucleic acids research. 2015;43(W1):W443–W447.
Yang H, Lou C, Sun L, Li J, Cai Y, Wang Z, et al. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics. 2019;35(6):1067–1069.
Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. Journal of combinatorial chemistry. 1999;1(1):55–68.
Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. Journal of medicinal chemistry. 2001;44(12):1841–1846.
Arnott JA, Planey SL. The inﬂuence of lipophilicity in drug discovery and design. Expert opinion on drug discovery. 2012;7(10):863–875.
Hildebrand JH. Solubility. xii. Regular solutions1. Journal of the American Chemical Society. 1929;51(1):66–80.
Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38(7-8):802–832.
Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug target insights. 2013;7:DTI–S12519.
Khushbu C, Roshni S, Anar P, Carol M, Mayuree P. Phytochemical and therapeutic potential of Piper longum Linn a review. International journal of research in Ayurveda and pharmacy. 2011;2(1):157–61.

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Virtual Screening of Phytochemical Compounds as Potential Inhibitors against SARS-CoV-2 Infection

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