key: cord-0789557-v986m9jd authors: Vijayakumar, Balaji Gowrivel; Ramesh, Deepthi; Joji, Annu; Jayachandra prakasan, Jayadharini; Kannan, Tharanikkarasu title: In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2 date: 2020-08-06 journal: Eur J Pharmacol DOI: 10.1016/j.ejphar.2020.173448 sha: c059bff4dc533a8d374a433d81cb2b0284c8bfa2 doc_id: 789557 cord_uid: v986m9jd Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (M(pro)) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that 30 compounds are capable of M(pro) deactivation as well as potentially lowering the efficiency of M(pro) function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential. Veber's rules (Veber et al., 2002) were used to check the drug-likeness. Flavonoids given in 112 Table 1 were analysed for their physicochemical properties and the results are epitomized in 113 Table 2 . The ADMET characteristics of the flavonoids were studied to understand their 114 pharmacokinetic profile and the results are given in Table 3 . 115 . Recent studies show us the spike protein is split into subunits 272 S1 and S2 by the host proteases; S1 is made up of two domains one C-terminal (CTD) and an 273 N-terminal (NTD) . The CTD is used by SARS-CoV-2 to bind to, and, it 274 subdomain is made up of two ß-strands attached to a flexible loop and, is primarily 276 responsible for receptor recognition and binding . Some of the residues 277 that the external subdomain of SARS-CoV-2 S1 CTD uses to bind to the receptor include, 278 Tyr453, Gly496, Gln498, Asn501, Gly502, Tyr503, and Tyr505 (Wang et al., 2020) . Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., 497 Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., 498 Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L.W., Xu, W., Xiao, G., Qin, C., Shi, Z., Molinspiration Cheminformatics Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Coronavirus main 403 proteinase (3CLpro) structure: basis for design of anti-SARS drugs Soy isoflavones and virus 406 infections Structural basis of flavonoids as dengue polymerase 409 inhibitors: insights from QSAR and docking studies Genistein inhibits African swine fever virus replication in vitro by disrupting viral 414 DNA synthesis Antiherpes evaluation of soybean isoflavonoids Structure of the RNA-dependent RNA polymerase from COVID-19 virus The origin, transmission and clinical therapies on coronavirus 478 disease 2019 (COVID-19) outbreak -an update on the status Synthesis and biological evaluation of phloridzin analogs 481 as human concentrative nucleoside transporter 3 (hCNT3) inhibitors Bioactive natural products with anti-484 herpes simplex virus properties Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic 490 494 therapy and cosmetics The 549 Signaling Pathways, and Therapeutic Targets of Antiviral Agents: Focusing on the 550 Antiviral Approaches and Clinical Perspectives of Anthocyanins in the Management 551 of Viral Diseases A structural analysis of M protein in coronavirus 556 assembly and morphology Chalcones isolated from Angelica keiskei inhibit 560 cysteine proteases of SARS-CoV pkCSM: Predicting Small-Molecule 563 Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures Coronavirus disease 2019 (COVID-19): first indication of 566 efficacy of Gene-Eden-VIR/Novirin in SARS-CoV-2 infection Apigenin restricts 569 FMDV infection and inhibits viral IRES driven translational activity. Viruses 7, 1613-Screening of Natural Products against Type II Transmembrane Serine Protease 573 (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2) Indole chalcones: Design, synthesis, in vitro and in silico evaluation against 577 Mycobacterium tuberculosis The Therapeutic Potential of Naringenin: A Review of Clinical Trials SWISS-MODEL: An automated 583 protein homology-modeling server Myricetin: A Dietary 586 Molecule with Diverse Biological Activities Mechanism for controlling the dimer-monomer switch 589 and coupling dimerization to catalysis of the severe acute respiratory syndrome 590 coronavirus 3C-like protease The catalysis of the SARS 3C-like protease is under extensive 593 regulation by its extra domain 595 Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic Coronavirus infectious 599 bronchitis virus non-structural proteins 8 and 12 form stable complex independent of 600 the non-translated regions of viral RNA and other viral proteins Novel chalcone derivatives containing a 1,2,4-triazine moiety: design, 604 synthesis Synthesis and antiviral 607 activity of novel myricetin derivatives containing ferulic acid amide scaffolds AutoDock Vina: Improving the speed and accuracy of docking 610 with a new scoring function, efficient optimization, and multithreading Antiviral Properties of the Natural Polyphenols Delphinidin Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus Molecular properties that influence the oral bioavailability of drug candidates Polymerases: Insights from Structure, Function and Evolution MERS-CoV spike protein: Targets for 624 vaccines and therapeutics Structural and Functional Basis of 628 SARS-CoV-2 Entry by Using Human ACE2 Eriodictyol inhibits IL-631 1β-induced inflammatory response in human osteoarthritis chondrocytes The N-terminal octapeptide acts as a dimerization inhibitor of SARS 636 coronavirus 3C-like proteinase Antifungal activity of 639 flavonoids against storage fungi of the genus Aspergillus Coronavirus pathogenesis A new coronavirus associated with 650 human respiratory disease in China Anti-AIDS agents 54. A potent anti HIV chalcone and flavonoids from genus Desmos Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses 8, 6 Antiviral Activity of Polymethoxylated 660 Flavones from "Guangchenpi", the Edible and Medicinal Pericarps of Citrus reticulata 661 'Chachi' derived from traditional chinese medicines, show roles in the 665 differentiation of neurons: Possible targets in developing health food products The crystal 669 structures of severe acute respiratory syndrome virus main protease Structural basis for inhibition 675 of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir Antibacterial Activities of 678 Flavonoids: Structure-Activity Relationship and Mechanism Anti-Inflammatory 681 activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and 682 liquiritigenin, in BV2 cells and mice liver Antiviral activity of four types of bioflavonoid against dengue virus type-2 Angiotensin-converting 688 enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential 689 therapeutic target Crystal structure of SARS-CoV-2 main protease provides a 693 basis for design of improved alpha-ketoamide inhibitors Effect of Eriodictyol on Glucose Uptake and Insulin Resistance 697 in Vitro Apigenin 700 Inhibits Enterovirus-71 Infection by Disrupting Viral RNA Association with trans Acting Factors A pneumonia 706 outbreak associated with a new coronavirus of probable bat origin Highlights • In silico evaluation of natural flavonoids and synthetic indole chalcones against homology modelled SARS-CoV-2 proteins (M pro , rdrp and S proteins) was carried