Molecular docking, molecular dynamic and drug-likeness studies of natural flavonoids as inhibitors for SARS-CoV-2 main protease (Mpro)
Molecular docking, molecular dynamic and drug-likeness studies of natural flavonoids as inhibitors for SARS-CoV-2 main protease (Mpro)
The emergence of the global pandemic COVID-19 lead to a huge demand for the therapeutic agent to combat the disease. Since the FDA approval of some of HIV-1 main protease inhibitors such as ritonavir lopinavir to treat COVID-19, the investigation of anti-HIV inhibitor to inhibit SARS-CoV-2 main protease (Mpro) is getting considerably much attention. This study evaluates the potency of sixteen selected natural flavonoids which were previously reported active to block HIV-1 protease as potential inhibitors of SARS-CoV-2 Mpro. The molecular docking and dynamic study were completed to know the binding affinity and stability of the protein-ligand complex via docking study along with molecular dynamic simulations. Moreover, drug-likeness was also evaluated through via ADMET evaluation. This study revealed robinin (6), a flavonol molecule with linked to galactose-rhamnose at C3 and rhamnose molecule at C7, exhibited the highest binding affinity (-9 kcal/mol) among others. The amino acids that interacted with robinin were Asn142; Gly143; Arg188; Thr190. The binding affinity of robinin surpassed the binding affinity of ritonavir (-7.7 kcal/mol) and lopinavir (-8.2 kcal/mol). The replacement of the hydroxyl group from the flavonoid skeleton at C7, C-4’ was proposed to affect the binding affinity. The free hydroxyl group particularly in A ring and the position of the hydroxyl group were important to improve the binding affinity. The molecular dynamic simulation showed the stability of Mpro-robinin during the simulation period. The ADME evaluation referring to Lipinski`s rule of 5 revealed that the flavonoids (2,5,6,9,10,13,14,15) show low oral bioavailability and absorption. Robinin exhibited a good druglikeness score (value:1) with an unconcerned level of acute toxicity. From this study, it was concluded that robinin showed the most potent natural flavonoids studied to inhibit SASR-CoV-2 Mpro by both docking study and ADME/tox properties evaluation.
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- [1] Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Alliano J, Bhattoa HP. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020; 12(4): 988.
- [2] Mouffouk C, Mouffouk S, Mouffouk C, Hambaba, Haba H. Flavonols as potential antiviral drugs targeting SARSCoV-2 proteases (3CLpro and PLpro), spike protein, RNA-dependent RNA polymerase (RdRp) and angiotensinconverting enzyme II receptor (ACE2). Elsevier B.V. 2021; 891: 173759.
- [3] Doremallen NV, Bushmaker T. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N. Engl J Med. 2020; 382: 1564-1567.
- [4] Mousavizadeh L, Ghasemi S, Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol. Immunol. Infect. 2021; 54(2): 1–4.
- [5] Chang KO, Kim Y, Lovell S, Rathnayake AD, and Groutas WC. Antiviral drug discovery: Norovirus proteases and development of inhibitors. Viruses. 2019; 11(2): 1-14.
- [6] Gyebi GA, Ogunro OB, Adegunloye AP, Ogunyemi OM, Afolabi SO. Potential inhibitors of coronavirus 3- chymotrypsin-like protease (3CLpro): an in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn. 2020; 39(9): 3396-3408.
- [7] Goyal B and Goyal D, Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential BroadSpectrum Therapeutic Strategy. ACS Comb Sci. 2020; 22(6): 297–305.
- [8] Swain SS, Singh SR, Sahoo A, Hussain T, Pati S. Anti-HIV-drug and phyto-flavonoid combination against SARSCoV-2: a molecular docking-simulation base assessment. J Biomol Struct Dyn. 2021; 1-14.
- [9] Rabby MII. Current drugs with potential for treatment of covid-19: A literature review. J Pharm Pharm Sci. 2020; 23(1): 58–64.
- [10] Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S. Potential Inhibitor of COVID-19 Main Protease ( M pro ) from Several Medicinal Plant Compounds by Molecular Docking Study. Preprints. 2020: 1–14.
- [11] Lokhande KB, Doiphode S, Vyas R, Swamy KV. Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19. J Biomol Struct Dyn. 2020; 1–12.
- [12] Mahdi M, Mótyán JA, Szojka ZI, Golda M, Miczi M, Tőzsér M. Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2′s main protease. Virol J. 2020; 17(1): 190.
- [13] Zhou et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798): 270–273.
- [14] Kraus M, Bader J, Overkleeft H, and Driessen C. Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance. Blood Cancer J. 2013; 3(3): 1–9.
- [15] Zhong DS et al. HIV protease inhibitor ritonavir induces cytotoxicity of human endothelial cells. Arterioscler Thromb Vasc Biol. 2002; 22(10): 1560-1566.
- [16] Saravanan D, Thirumalai D, and Asharani IV. Anti-HIV flavonoids from natural products: A systematic review. Int J Res Pharm Sci. 2015; 6(3): 248–255.
- [17] Ko YJ, Oh HJ, Ahn HM, Kang HJ, Kim JH, Ko YH.Flavonoids as Potential Inhibitors of Retroviral Enzymes. J Korean Soc Appl Biol Chem. 2009; 52(4): 321–326.
- [18] Lee JS , Kim HJ, Lee YS. A new Anti-HIV Flavonoid Glucuronide from Chrysanthemum morifolium. Planta Med. 2003; 69(9): 859–861.
- [19] Xu HX, Wan M, Dong H, Hay-But PP, Foo LY. Inhibitory activity of flavonoids and tannins against HIV-1 protease. Biol Pharm Bull. 2000. 2000; 23(9):1072-1076.
- [20] Owis AI, El-Hawary MS, Amir ED, Aly OM, Abdelmohsen UR, Kamel MS. Molecular docking reveals the potential of Salvadora persica flavonoids to inhibit COVID-19 virus main protease. RSC Adv. 2020; 10(33): 19570–19575.
- [21] Zakaryan H, Arabyan E, Oo A, Zandi K. Flavonoids: promising natural compounds against viral infections. Arch Virol. 2017; 162(9): 2539–2551.
- [22] Phosrithong N, Ungwitayatorn J. Molecular docking study on anticancer activity of plant-derived natural products. Med Chem Res. 2010; 19(8): 817–835.
- [23] Áy É, Hunyadi A, Mezei M, Minárovits J, Hohmann J. Flavonol 7- O -Glucoside Herbacitrin Inhibits HIV-1 Replication through Simultaneous Integrase and Reverse Transcriptase Inhibition. Evidence-based Complement. Altern Med. 2019; 2019: 1-6.
- [24] Pastor N, Collado MC, Manzoni P. Phytonutrient and nutraceutical action against COVID-19: Current review of characteristics and benefits. Nutrients. 2021; 13(2): 1–10.
- [25] Omrani M, Bayati M, Mehrbod P, Bardazard KA, Nejad-ebrahimi S. Natural products as inhibitors of COVID-19 main protease – A virtual screening by molecular docking. Pharm Sci. 2021; 27(Suppl 1): 1-37.
- [26] Lipinski CA, Lombardo F, Dominy BW, and Feeney FJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2012; 64(2012): 4– 17.
- [27] Oktavia L, Krishna VS, Rekha EM, Fathoni A, Sriram D, Agusta A. Anti-mycobacterial activity of two natural Bisanthraquinones: (+)-1,1′-Bislunatin and (+)-2,2′-Epicytoskyrin A. IOP Conf Ser Earth Environ Sci. 2000; 591(2020): 1-14.
- [28] Zerroug A, Belaidi S, BenBrahim I, Sinha L, Chtita S. Virtual screening in drug-likeness and structure/activity relationship of pyridazine derivatives as Anti-Alzheimer drugs. J King Saud Univ - Sci. 2019; 31(4): 595–601.
- [29] Chandrasekaran K, Kumar RT. Molecular properties prediction , docking studies and antimicrobial screening of ornidazole and its derivatives. J Chem Pharm Res. 2016; 8(3):849–861.
- [30] Schaftenaar G, Vlieg JD. Quantum mechanical polar surface area. J Comput Aided Mol Des. 2012; 26: 311–318.
- [31] Gupta M, Lee HJ, Barden CJ , Weaver DF. The Blood-Brain Barrier (BBB) Score. J Med Chem. 2019; 62(21): 9824– 9836.
- [32] Chen R et al. Potential toxicity of quercetin: The repression of mitochondrial copy number via decreased POLG expression and excessive TFAM expression in irradiated murine bone marrow. Toxicol Reports. 2014; 1: 450–458.
- [33] Choi KY, Liu G, Lee S, Chen X. Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. Nanoscale. 2012; 4(2): 330–342.
- [34] Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2009; 31(2): 455–461.
- [35] Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng Des Sel. 1995; 8(2): 127–134.
- [36] Phillips JC et al. Scalable molecular dynamics with NAMD. J ComputChem. 2005; 26(16): 1781-1802.
- [37] Jo S, Kim T, Iyer VG, Im W. CHARMM-GUI: a web-based graphical user interface for CHARMM.J Comput Chem. 2008; 29(11): 1859-1865.
- [38] Humphrey W, Dalke A, Schulten K. VMD: Visual molecular dynamics. J Mol Graph. 1996; 14(1): 33-38.