Background: Human angiotensin-converting enzyme-2 (ACE-2) and severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) main protease (Mpro) have been established as the prime targets to restrict viral invasion and replication inside the host, respectively.
Methods: The current study delineated the SARS-CoV-2 Mpro as well as human ACE-2 inhibitory potential of carotenoids and polyphenols from tomato (Solanum lycopersicum L.) via in-silico interaction studies.
Results: Our drug-likeness studies showed that the selected carotenoids and polyphenols exhibited acceptable Lipinski’s score and ADME determinants. Further, in-silico molecular modelling studies revealed that β-carotene, among other carotenoids, topped the binding score (ΔG: -6.75 kcal/mol; Ki: 11.32 µM) against SARS-CoV-2 Mpro, whereas, cyanidin was the best inhibitor of SARS-CoV-2 Mpro (-7.24 kcal/mol; Ki: 4.92 µM) amongst polyphenols. Similarly, α-carotene from carotenoids exhibited strongest human ACE-2 inhibitory activity (ΔG: -8.85 kcal/mol; Ki: 326.13 µM), whereas, cyanidin from polyphenols showed best binding affinity against human ACE-2 (ΔG: -7.24 kcal/mol; Ki: 4.89 µM). In contrast, 6-(ethylamino)-pyridine-3-carbonitrile, standard inhibitor of SARS-CoV-2 Mpro, exhibited comparatively weaker binding (ΔG: -4.78 kcal/mol; Ki: 267.49 µM), whereas, telmisartan (reference ACE-2 inhibitor) also exhibited lesser affinity (ΔG: -6.40 kcal/mol; Ki: 20.40 µM). Further exploration via MDS studies also validated the dynamic behavior and stability of protein-ligand complexes as evident by desirable RMSD, RMSF, Rg, and SASA.
Conclusion: The current study established carotenoids and polyphenols from S. lycopersicum L. as finer substitutes of reference standards against SARS-CoV-2 Mpro and human ACE-2 activity in combating SARS-CoV-2 infection.
| [1] |
Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141–154.
|
| [2] |
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513.
|
| [3] |
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–574.
|
| [4] |
Chan JFW, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microb Infect. 2020;9(1):221–236.
|
| [5] |
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACe2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.e8.
|
| [6] |
Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACe2 receptor. Nature. 2020;581(7807):215–220.
|
| [7] |
Bian J, Li Z. Angiotensin-converting enzyme 2 (ACe2): SARS-CoV-2 receptor and RAS modulator. Acta Pharm Sin B. 2021;11(1):1–12.
|
| [8] |
Davidson AM, Wysocki J, Batlle D. Interaction of SARS-CoV-2 and other coronavirus with ACE (angiotensin-converting enzyme)-2 as their main receptor: therapeutic implications. Hypertension. 2020;76(5):1339–1349.
|
| [9] |
Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020;10(4):313–319.
|
| [10] |
Ullrich S, Nitsche C. The SARS-CoV-2 main protease as drug target. Bioorg Med Chem Lett. 2020;30(17):127377.
|
| [11] |
Muramatsu T, Takemoto C, Kim YT, et al. SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016;113(46):12997–13002.
|
| [12] |
Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409–412.
|
| [13] |
Keretsu S, Bhujbal SP, Cho SJ. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Sci Rep. 2020;10(1).
|
| [14] |
Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363–374.
|
| [15] |
Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762–768.
|
| [16] |
Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420–422.
|
| [17] |
Zheng HY, Zhang M, Yang CX, et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell Mol Immunol. 2020;17(5):541–543.
|
| [18] |
Ahmad P, Alvi SS, Iqbal D, Khan MS. Insights into pharmacological mechanisms of polydatin in targeting risk factors-mediated atherosclerosis. Life Sci. 2020;254:117756.
|
| [19] |
Akhter F, Alvi SS, Ahmad P, Iqbal D, Alshehri BM, Khan MS. Therapeutic efficacy of Boerhaavia diffusa (Linn.) root methanolic extract in attenuating streptozotocin-induced diabetes, diabetes-linked hyperlipidemia and oxidative-stress in rats. Biomed Res Ther. 2019;6(7):3293–3306.
|
| [20] |
Ahmad P, Alvi SS, Khan MS. Functioning of organosulfur compounds from garlic (allium sativum linn) in targeting risk factor-mediated atherosclerosis: a cross talk between alternative and modern medicine. In: Natural Bio-Active Compounds. Springer Singapore; 2019:561–585.
|
| [21] |
Alvi SS, Ahmad P, Ishrat M, Iqbal D, Khan MS. Secondary metabolites from rosemary(Rosmarinus officinalis L.): structure, biochemistry and therapeutic implications against neurodegenerative diseases. Natural Bio-Active Compounds: Chemistry, Pharmacology and Health Care Practices. 2019;2:1–24.
|
| [22] |
Nabi R, Alvi SS, Shah A, et al. Modulatory role of HMG-CoA reductase inhibitors and ezetimibe on LDL-AGEs-induced ROS generation and RAGE-associated signalling in HEK-293 Cells. Life Sci. 2019;235:116823.
|
| [23] |
Nabi R, Alvi SS, Khan RH, Ahmad S, Ahmad S, Khan MS. Antiglycation study of HMG-R inhibitors and tocotrienol against glycated BSA and LDL: a comparative study. Int J Biol Macromol. 2018;116:983–992.
|
| [24] |
Hashim A, Alvi SS, Ansari IA, Salman Khan M. Phyllanthus virgatus forst extract and it’s partially purified fraction ameliorates oxidative stress and retino-nephropathic architecture in streptozotocin-induced diabetic rats. Pak J Pharm Sci. 2019;32(6):2697–2708.
|
| [25] |
Wang G, Liu Z, Li M, et al. Ginkgolide B mediated alleviation of inflammatory cascades and altered lipid metabolism in HUVECs via targeting PCSK-9 expression and functionality. BioMed Res Int. 2019;2019.
|
| [26] |
Khushtar M, Siddiqui HH, Dixit RK, Alvi SS. Curative effects of triphala extract against swim stress-induced gastric ulcers via reduced ulcer index, strengthened gastric mucosa and improved redox state in rats. Indian J Pharmaceut Sci. 2023;85(1):176–188.
|
| [27] |
Alvi SS, Ansari IA, Ahmad MK, Iqbal J, Khan MS. Lycopene amends LPS induced oxidative stress and hypertriglyceridemia via modulating PCSK-9 expression and Apo-CIII mediated lipoprotein lipase activity. Biomed Pharmacother. 2017;96:1082–1093.
|
| [28] |
Alvi SS, Ansari IA, Khan I, Iqbal J, Khan MS. Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia. Free Radic Biol Med. 2017;108:394–403.
|
| [29] |
Waiz M, Alvi SS, Khan MS. Potential dual inhibitors of PCSK-9 and HMG-R from natural sources in cardiovascular risk management. EXCLI J. 2022;21:47–76. https://doi.org/10.17179/EXCLi2021-4453.
|
| [30] |
Martí R, Roselló S, Cebolla-Cornejo J. Tomato as a source of carotenoids and polyphenols targeted to cancer prevention. Cancers. 2016;8(6).
|
| [31] |
Alvi SS, Iqbal D, Ahmad S, Khan MS. Molecular rationale delineating the role of lycopene as a potent HMG-CoA reductase inhibitor: in vitro and in silico study. Nat Prod Res. 2016;30(18):2111–2114.
|
| [32] |
Alvi SS, Ansari IA, Khan MS. Pleiotropic role of lycopene in protecting various risk factors mediated atherosclerosis. Ann Phytomed. 2015;4(1):54–60.
|
| [33] |
Ahmad P, Alvi SS, Iqbal J, Khan MS. Target-based virtual and biochemical screening against HMG-CoA reductase reveals allium sativum-derived organosulfur compound N-acetyl cysteine as a cardioprotective agent. Rev Bras Farmacogn. 2022:1–12. Published online October 27.
|
| [34] |
Ahmad P, Alvi SS, Iqbal J, Khan MS. Identification and evaluation of natural organosulfur compounds as potential dual inhibitors of α-amylase and α-glucosidase activity: an in-silico and in-vitro approach. Med Chem Res. 2021;30(12):2184–2202.
|
| [35] |
Asif M, Alvi SS, Azaz T, et al. Novel functionalized spiro [Indoline-3, 5′-pyrroline]-2, 2′dione derivatives: synthesis, characterization, drug-likeness, ADME, and anticancer potential. Int J Mol Sci. 2023;24(8):7336.
|
| [36] |
Ahmad S, Nabi R, Alvi SS, et al. Carvacrol protects against carbonyl osmolyte-induced structural modifications and aggregation to serum albumin: insights from physicochemical and molecular interaction studies. Int J Biol Macromol. 2022;213:663–674.
|
| [37] |
Ahmad P, Alvi SS, Waiz M, Khan MS, Ahmad S, Khan MS. Naturally occurring organosulfur compounds effectively inhibits PCSK-9 activity and restrict PCSK-9-LDL-receptor interaction via in-silico and in-vitro approach. Nat Prod Res. 2023:1–10.
|
| [38] |
Zhang D, Lazim R. Application of conventional molecular dynamics simulation in evaluating the stability of apomyoglobin in urea solution. Sci Rep. 2017;7(1):44651.
|
| [39] |
Schneider P, Walters WP, Plowright AT, et al. Rethinking drug design in the artificial intelligence era. Nat Rev Drug Discov. 2020;19(5):353–364.
|
| [40] |
Hessler G, Baringhaus KH. Artificial intelligence in drug design. Molecules. 2018;23(10):2520.
|
| [41] |
Milani A, Basirnejad M, Shahbazi S, Bolhassani A. Carotenoids: biochemistry, pharmacology and treatment. Br J Pharmacol. 2017;174(11):1290–1324.
|
| [42] |
Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2005;2(4):541–553.
|
| [43] |
Hitchcock SA, Pennington LD. Structure-brain exposure relationships. J Med Chem. 2006;49(26):7559–7583.
|
| [44] |
Ditzinger F, Price DJ, Ilie AR, et al. Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches–a PEARRL review. J Pharm Pharmacol. 2019;71(4):464–482.
|
| [45] |
Prasanna S, Doerksen R. Topological polar surface area: a useful descriptor in 2D-QSAR. Curr Med Chem. 2008;16(1):21–41.
|
| [46] |
Ma XL, Chen C, Yang J. Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacol Sin. 2005;26(4):500–512.
|
| [47] |
Leão RP, Cruz JV, da Costa GV, et al. Identification of new rofecoxib-based cyclooxygenase-2 inhibitors: a bioinformatics approach. Pharmaceuticals. 2020;13(9):1–26.
|
| [48] |
Bittermann K, Goss KU. Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: a mechanistic modelHofmann A, ed. PLoS One. 2017;12(12): e0190319.
|
| [49] |
Volpe DA. Variability in caco-2 and MDCK cell-based intestinal permeability assays. J Pharmaceut Sci. 2008;97(2):712–725.
|
| [50] |
Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharmaceut Sci. 2000;10(3):195–204.
|
| [51] |
Lundborg M, Wennberg CL, Narangifard A, Lindahl E, Norlén L. Predicting drug permeability through skin using molecular dynamics simulation. J Contr Release. 2018;283:269–279.
|
| [52] |
Chen CP, Chen CC, Huang CW, Chang YC. Evaluating molecular properties involved in transport of small molecules in stratum corneum: a quantitative structure-activity relationship for skin permeability. Molecules. 2018;23(4):911.
|
| [53] |
Roberts JA, Pea F, Lipman J. The clinical relevance of plasma protein binding changes. Clin Pharmacokinet. 2013;52(1):1–8.
|
| [54] |
Gurevich KG. Effect of blood protein concentrations on drug-dosing regimes: practical guidance. Theor Biol Med Model. 2013;10(1):20.
|
| [55] |
Zhao YH, Le J, Abraham MH, et al. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure -activity relationship (QSAR) with the Abraham descriptors. J Pharmaceut Sci. 2001;90(6):749–784.
|
| [56] |
Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF. New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme Structural features of CYP2D6 B. Wang et al. Drug Metab Rev. 2009;41(4):573–643.
|
| [57] |
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–141.
|
| [58] |
Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metabol Pharmacokinet. 2012;27(1):55–67.
|
| [59] |
Walko CM, McLeod H. Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment. Pharmacogenomics. 2012;13(6):691–697.
|
| [60] |
Neves Cruz J, Santana De Oliveira M, Gomes Silva S, et al. Insight into the interaction mechanism of nicotine, NNK, and NNN with cytochrome P450 2A13 based on molecular dynamics simulation. J Chem Inf Model. 2020;60(2):766–776.
|
| [61] |
Sacco MD, Ma C, Lagarias P, et al. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L. Sci Adv. 2020;6(50):eabe0751.
|
| [62] |
Zaki AA, Ashour A, Elhady SS, Darwish KM, Al-Karmalawy AA. Calendulaglycoside A showing potential activity against SARS-CoV-2 main protease: molecular docking, molecular dynamics, and SAR studies. J Tradit Complement Med. 2021. Published online May 17.
|
| [63] |
Bharadwaj S, El-Kafrawy SA, Alandijany TA, et al. Structure-based identification of natural products as sars-cov-2 mpro antagonist from echinacea angustifolia using computational approaches. Viruses. 2021;13(2).
|
| [64] |
Vardhan S, Sahoo SK. Virtual screening by targeting proteolytic sites of furin and TMPRSS2 to propose potential compounds obstructing the entry of SARS-CoV-2 virus into human host cells. J Tradit Complement Med. 2021. Published online.
|
| [65] |
Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA. 2020;117(21):11727–11734.
|
| [66] |
Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681–687. 2020 265.
|
| [67] |
Basu A, Sarkar A, Maulik U. Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACe2. Sci Rep. 2020;10(1):1–15.
|
| [68] |
Abubakar MB, Usman D, El-Saber Batiha G, et al. Natural products modulating angiotensin converting enzyme 2 (ACe2) as potential COVID-19 therapies. Front Pharmacol. 2021;12:629935.
|
| [69] |
Arnittali M, Rissanou AN, Harmandaris V. Structure of biomolecules through molecular dynamics simulations. Procedia Comput Sci. 2019;156:69–78.
|
| [70] |
Martínez L. Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. Kleinjung J, ed. PLoS One. 2015;10(3):e0119264.
|
| [71] |
Alvi SS, Nabi R, Khan MS, Akhter F, Ahmad S, Khan MS. Glycyrrhizic acid scavenges reactive carbonyl species and attenuates glycation-induced multiple protein modification: an in vitro and in silico study. In: Tatone C, ed. Oxid Med Cell Longev. 2021. 2021:1–14.
|
| [72] |
Nabi R, Alvi SS, Shah MS, et al. A biochemical & biophysical study on in-vitro antiglycating potential of iridin against D-Ribose modified BSA. Arch Biochem Biophys. 2020;686:108373.
|
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