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As Potential Targets Against SARS-Cov-2 Viral Proteins ew Vol 5 | Issue 1 | Pages 214-223 Journal of Clinical Anesthesia and Pain Management ISSN: 2578-658X Original Article DOI: 10.36959/377/356 In Silico Identification of Apigenin and Narcissin (Food- Flavonoids) as Potential Targets Against SARS-CoV-2 Viral Proteins: Comparison with the Effect of Remdesivir Vincent Brice Ayissi Owona1*, Borris RT Galani2 and Paul Fewou Moundipa1 1Laboratory of Molecular Pharmacology and Toxicology, Department of Biochemistry, Faculty of Science, Check for updates University of Yaounde 1, Yaounde, Cameroon 2Laboratory of Applied Biochemistry, Department of Biological Sciences, Faculty of Science, University of Ngaoundere, Ngaoundere, Cameroon Abstract Background: In this study, we demonstrate the potential role of Narcissin and apigenin, two natural flavonoids found in fruits and foods, as candidate compounds in the treatment against the novel corona virus infection using in silico tools. Methods: We have used computational molecular docking screening (Molegro Virtual Docker) to study the effect of selected flavonoids on main viral proteins including MERS-COV spike-RBD, RNA-polymerase, viral main protease, and papain-like protease. A grid resolution of 30 A° was used, together with an MM2 force field for energy minimization. Moreover, the MolDock Score and ReRank score were used as scoring functions. The results obtained were compared to those of Remdesivir, a drug under investigation for Covid-19 treatment. Results: Narcissin, Apigenin and Remdesivir were identified as strong inhibitors of Covid-19 proteins with MolDock scores of: MERS-COV Spike-RBD, PDB: 4KRO (-101.704, -61.069, -15.96), Papain-like protease MERS, PDB: 4P16 (-91.462, -47.314, -43.64), SARS-COV-2 main protease in complex with inhibitor UAW246, PDB: 6XBG (-151.124, -98.20, -150.12) respectively for the three drugs. As far as 7BZ5 (Spike receptor binding domain) and 7BTF (SARS-COV-2-RNA polymerase) proteins are concerned, Remdesivir showed inhibitory effect higher than Narcissin and Apigenin for 7BZ5 (-85.98, -44.78, -60.074), 7BTF (-113.44, -109.32, -93.403) even though the binding affinity towards 7BTF (RNA polymerase) was higher for Narcissin and Apigenin. The results showed that Narcissin has high affinity towards 6XBG as it showed 12 hydrogen bonds with amino acids Phe3, Lys5 and Glu288, while showing 8 hydrogen bonds with 7BTF (RNA polymerase). Apigenin showed 6 hydrogen bonds with amino acids Gly 138 and Glu 288 for 6XBG and 5 hydrogen bonds with amino acids Asn459, Thr462, Arg349 and Met 629 for 7BTF. Conclusion: From in silico analysis, it was concluded that Narcissin and Apigenin are potential Covid-19 viral inhibitors by directly binding to RNA polymerase and key viral proteins such as the main protease and the spike-RBD. Both flavonoids had high affinity and inhibitory potential than the reference drug used in clinical studies. Narcissin and apigenin are therefore predicted after further confirmation as potent candidate drugs to enter clinical studies as efficient drugs against the novel Covid-19. Keywords Apigenin, Narcissin, Remdesivir, Molecular docking, SARS-CoV2 proteins Introduction *Corresponding author: Dr. Vincent Brice Owona Ayissi, Labo- In late 2019, an ongoing outbreak emerged from China ratory of Molecular Pharmacology and Toxicology, Department Wuhan city. After a noticeably short period of time, what of Biochemistry, University of Yaounde 1, Yaounde, Cameroon has become a pandemic had spread across the world with an Accepted: March 20, 2021 alarming daily increase of cases and deaths [1,2]. As of Octo- March 22, 2021 ber 2020, 34,986,502 Covid-19 positive cases were reported Published online: with 6 million recovered and 1,034,240 deaths. Fortunately, Citation: Owona VBA, Galani BRT, Moundipa PF (2021) In Silico the World Health Organization (WHO) has taken several mea- Identification of Apigenin and Narcissin (Food-Flavonoids) as sures to help reduce disease transmission and control the Potential Targets Against SARS-CoV-2 Viral Proteins: Compar- outbreak. Nevertheless, the number of cases is increasing, ison with the Effect of Remdesivir. J Clin Anesth Pain Manag 5(1):214-223 and it appears that well equipped health systems are becom- Copyright: © 2021 Owona VBA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and SCHOLARS.DIRECT reproduction in any medium, provided the original author and source are credited. Open Access | Page 214 | Citation: Owona VBA, Galani BRT, Moundipa PF (2021) In Silico Identification of Apigenin and Narcissin (Food-Flavonoids) as Potential Targets Against SARS-CoV-2 Viral Proteins: Comparison with the Effect of Remdesivir. J Clin Anesth Pain Manag 5(1):214-223 ing overwhelmed with the situation. It therefore appears that infection is Narcissin (Isorhamnetin-3-O-rutinoside), also the identification of safe and effective anti-viral compounds known as Narcissoside, has been identified and isolated from could open the way to the finding of an appropriate treat- several plants and leaves including the leaves of Manihot es- ment by targeting SARS-CoV-2 viral components. cylenta Crantz also known as cassava leaves which are highly consumed in sub-Saharan Africa [19]. Several viral proteins have been identified and are under investigation in laboratories across the world. Amongst them, So far, no treatment has been found against Covid-19 in- the Spike-RBD is the viral protein that binds to the host recep- fection. Remdesivir has entered clinical trials in the United tor angiotensin-converting enzyme-2 via its receptor-bind- States of America and China, with the purpose of using the ing-domain (RBD), and thus is believed to be a major target drug as a therapeutic for Covid-19. Unfortunately, prelimi- to block viral entry. The SARS-Cov2 main protease is a key nary clinical trials results suggest only some benefit-risk pro- protein in the virus life cycle and is therefore an attractive file of the drug on severe Covid-19 patients [20]. Indeed, -re drug target among coronaviruses since it plays an essential ported adverse effects in patients taking Remdesivir included role in processing the polyproteins that are translated from nausea, acute respiratory failure, and elevated liver enzymes. the viral RNA. The RNA polymerase of SARS-CoV-2 plays a piv- In the present work, we have used in silico approach to otal role in viral replication and as such, is a potential target identify potential viral inhibitors from flavonoids available in for anti-SARS therapy. Other proteins include virally encoded daily consumed fruits and vegetables. Cheap, safe, and ef- cysteine proteases. fective inhibitors of SARS-CoV-2 could help as effective treat- Natural compounds may provide an alternative approach ment against the Covid-19 pandemic. for the discovery of new drugs with antiviral activities. This is the case of flavonoids which are reported to have antiviral Material and Methods effects against SARS- and MERS-CoV respectively [3]. Coro- In silico-molecular docking navirus have always been targets of several active flavonoids by directly inhibiting the protein 3LPro (3-chymotrypsin-like In this work, we used MVD software which provides very protease) and Papain-like protease (PLPro). This is the case accurate predictions of ligand binding modes (87%) in com- of herbacetin, rhoifolin and pectolonarin, which were found parison to other docking softwares [21]. to efficiently block the enzymatic activity of SARS-COV 3CL- Ligand preparation Pro [4]. An in silico and in vitro recent study also reported the inhibitory effect of quercetin, epigallo catechin gallate, Gal- The mol files used for docking were obtained from locatechin gallate and Rutin on the same protease (3CLPro) Molview, which was used to draw the structures of ligands [5,6]. Medicinal plants and compounds from Chinese medi- when necessary. Narcissin, Apigenin and Remdesivir were cine have shown promising effects for SARS-CoV-2 potential identified from PubChem chemical database. The structures treatment. This is the case of Glycyrrhizin which is reported were confirmed with Molview software and the energy mini- to inhibit the replication of SARS-associated corona viruses mization performed using the MM2 force field and saved as a in vitro [7,8]. Moreover, high doses of the drug have been .MOL format. Energy minimization was done to help the dock- used in clinical trials and was reported effective for SARS ing programme in the identification of the bioactive conform- treatment [9,10]. Herperidin, a flavonoid found in citrus fruits ers. The missing charges and hybridization states of different is an inhibitor of ACE2, and thereby blocks the infection of ligands structure were assigned with the help of the MVD SARS-CoV-2 [11] and cleaves 3CLpro in cell-based assays [12]. (Molview Virtual Docker) software. The major advantage of Baicalin another flavone showed antiviral activities against 10 MVD is that it can assign the missing bond orders, charges, clinical isolates of SARS-CoV [13]. Finally, quercetin demon- bonds and hybridization states of the investigated ligands. strated antiviral effect by inhibiting 3CLpro of SARS-CoV [14] Protein preparation and by blocking the entry of SARS-CoV into host cells [15]. The three-dimensional crystal structure (3D structure) of For an exceptionally long time, drugs were identified ran- different receptors was retrieved from the protein data bank domly and by chance. Since the development of computed (PDB) (http://www.rcsb.org). We have chosen respectively: aided methods, the process of drug discovery has been con- Papain-like protease of MERS coronavirus (PDB ID: 4P16), siderably speeded up and Molecular Docking approaches MERS-CoV spike-RBD (PDB ID: 4KR0), SARS-CoV-2 main pro- could play a pivotal role in identifying drugs before entering tease (PDB ID: 6XBG), Covid-19 virus spike receptor binding pharmacological and clinical trials. domain (PDB ID: 7BZ5) and SARS-CoV-2-RNA-dependent For centuries, medicinal plants and foods have been re- RNA Polymerase (PDB ID: 7BTF).
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