Erman Salih İSTİFLİ, Bektaş TEPE, Cengiz SARIKÜRKCÜ, Arzuhan ŞIHOĞLU TEPE

Interaction of certain monoterpenoid hydrocarbons with the receptor binding domain of 2019 novel coronavirus (2019-nCoV), transmembrane serine protease 2 (TMPRSS2), cathepsin B, and cathepsin L (CatB/L) and their pharmacokinetic properties

As of June 2020, the coronavirus disease 19 (COVID-19) caused by the 2019 new type coronavirus (2019-nCoV) infected more than 7,000,000 people worldwide and caused the death of more than 400,000 people. The aim of this study was to investigate the molecular interactions between monoterpenoids and spike protein of 2019-nCoV together with the cellular proteases [transmembrane serine protease 2 (TMPRSS2), cathepsin B (CatB), and cathepsin L (CatL)]. As a result of the relative binding capacity index (RBCI) analysis, carvone was found to be the most effective molecule against all targets when binding energy and predicted (theoretical) IC50 data were evaluated together. It was found to exhibit drug-likeness property according to the Lipinski’s rule-of-five. Carvone has also been determined to be able to cross the blood-brain barrier (BBB) effectively, not a substrate for P-glycoprotein (P-gp), not to inhibit any of the cytochrome P molecules, and to have no toxic effects even on liver cells. In addition, the LD50 dose of carvone in rats was 1.707 mol/kg. Due to its interaction profile with target proteins and excellent pharmacokinetic properties, it has been concluded that carvone can be considered as an alternative agent in drug development studies against 2019-nCoV.

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Andersen K, Rambaut A, Lipkin W, Holmes E, Garry R (2020). The proximal origin of SARS-CoV-2. Nature Medicine 26: 450-452.
Camacho C, Coulouris G, Avagyan V, Ma N, Papadopoulos J et al. (2009). BLAST+: architecture and applications. BMC Bioinformatics 10: 421.
Chan JF-W, Yuan S, Kok K-H, To KK-W, Chu H et al. (2020). A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. The Lancet 395: 514-523.
Colovos C, Yeates TO (1993). Verification of protein structures: patterns of nonbonded atomic interactions. Protein Science 2: 1511-1519.
Corman V, Lienau J, Witzenrath M (2019). Coronaviruses as the cause of respiratory infections. Der Internist 60: 1136-1145.
Daina A, Michielin O, Zoete V (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports 7: 42717.
Daina A, Michielin O, Zoete V (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research 47: W357-W364.
De Wit E, van Doremalen N, Falzarano D, Munster VJ (2016). SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology 14: 523-534.
Evans RM (1988). The steroid and thyroid hormone receptor superfamily. Science 240: 889-895.
Fehr AR, Channappanavar R, Perlman S (2017). Middle East respiratory syndrome: emergence of a pathogenic human coronavirus. Annual Review of Medicine 68: 387-399.
Glowacka I, Bertram S, Müller MA, Allen P, Soilleux E et al. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Journal of Virology 85: 4122-4134.
Greenspan PD, Clark KL, Tommasi RA, Cowen SD, McQuire LW et al. (2001). Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design. Journal of Medicinal Chemistry 44: 4524-4534.
Guan Y, Zheng B, He Y, Liu X, Zhuang Z et al. (2003). Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 302: 276-278.
Guex N, Peitsch MC, Schwede T (2009). Automated comparative protein structure modeling with SWISS-MODEL and SwissPdbViewer: a historical perspective. Electrophoresis 30: S162- 173.
Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R et al. (2011). Halogen bonding at the active sites of human cathepsin L and MEK1 kinase: efficient interactions in different environments. ChemMedChem 6 (11): 2048-2054.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181 (2): 271–280.e8.
Huang C, Wang Y, Li X, Ren L, Zhao J et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395 (10223): 497-506.
Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993). PROCHECK: a program to check the stereochemical quality of protein structures. Journal of Applied Crystallography 26: 283-291.
Lau SK, Woo PC, Li KS, Huang Y, Tsoi H-W et al. (2005). Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proceedings of the National Academy of Sciences 102 (39): 14040-14045.
Li F, Li W, Farzan M, Harrison SC (2005). Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309 (5742): 1864-1868.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK et al. (2003). Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450-454.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 23 (1-3): 3-25.
Matsuyama S, Nagata N, Shirato K, Kawase M, Takeda M et al. (2010). Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. Journal of Virology 84: 12658-12664.
Meneguzzo F, Ciriminna R, Zabini F, Pagliaro M (2020). Accelerated production of hesperidin-rich citrus pectin from waste citrus peel for prevention and therapy of COVID-19. Preprints. doi: 10.20944/preprints202003.0386.v1
Morris GM, Lim-Wilby M (2008). Molecular docking. Methods in Molecular Biology 443: 365-382.
Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E (2020). A novel coronavirus emerging in China—key questions for impact assessment. New England Journal of Medicine 382: 692-694.
Nasab RR, Hassanzadeh F, Khodarahmi GA, Rostami M, Mirzaei M et al. (2017). Docking study, synthesis and antimicrobial evaluation of some novel 4-anilinoquinazoline derivatives. Research in Pharmaceutical Sciences 12 (5): 425-433.
Nguyen PH, Sigdel KP, Schaefer KG, Mensah GAKet al. (2020). The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences. Biochemical Pharmacology 174: 113813 doi: 10.1016/j.bcp.2020.113813
Pedretti A, Villa L, Vistoli G (2004). VEGA--an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. Journal of ComputerAided Molecular Design 18: 167-173.
Pires DE, Blundell TL, Ascher DB (2015). pkCSM: predicting smallmolecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry 58: 4066-4072.
Prakash D, Suri S, Upadhyay G, Singh BN (2007). Total phenol, antioxidant and free radical scavenging activities of some medicinal plants. International Journal of Food Sciences and Nutrition 58: 18-28.
Rac A, Fulgosi H (2020). Qualitative and quantitative dataset of TROL protein interaction with C3 and C4 ferredoxin: NADP(+) oxidoreductases. Data in Brief 28: 105038.
Ramírez D, Caballero J (2018). Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data? Molecules 23: 1038.
Remmert M, Biegert A, Hauser A, Soding J (2011). HHblits: lightning-fast iterative protein sequence searching by HMMHMM alignment. Nature Methods 9: 173-175.
Rettie AE, Jones JP (2005). Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annual Reviews of Pharmacology and Toxicology 45: 477-494.
Ricci CG, Netz PA (2009). Docking studies on DNA-ligand interactions: building and application of a protocol to identify the binding mode. Journal of Chemical Information and Modeling 49: 1925-1935.
Sampangi-Ramaiah MH, Vishwakarma R, Shaanker RU (2020). Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 main protease. Current Science 118 (7): 1087-1092.
Sanner MF (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and Modelling 17: 57-61.
Sharma S (1996). Two group discriminant analysis. Applied multivariate techniques. New York, NY, USA: John Wiley & Sons, Inc, pp. 237-286.
Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S et al. (2011). A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. Journal of Virology 85: 873-882.
Singh BN, Singh B, Singh R, Prakash D, Dhakarey R et al. (2009). Oxidative DNA damage protective activity, antioxidant and anti-quorum sensing potentials of Moringa oleifera. Food and Chemical Toxicology 47: 1109-1116.
Singh BN, Singh B, Singh R, Prakash D, Sarma B et al. (2009). Antioxidant and anti-quorum sensing activities of green pod of Acacia nilotica L. Food and Chemical Toxicology 47 (4): 778-786.
Singh BN, Singh B, Singh R, Prakash D, Singh D et al. (2009). Polyphenolics from various extracts/fractions of red onion (Allium cepa) peel with potent antioxidant and antimutagenic activities. Food and Chemical Toxicology 47 (6): 1161-1167.
Singh HB, Singh BN, Singh SP, Nautiyal CS (2010). Solid-state cultivation of Trichoderma harzianum NBRI-1055 for modulating natural antioxidants in soybean seed matrix. Bioresource Technology 101 (16): 6444-6453.
Smith M, Smith JC (2020). Repurposing therapeutics for covid-19: Supercomputer-based docking to the sars-cov-2 viral spike protein and viral spike protein-human ace2 interface. ChemRxiv. doi: 10.26434/chemrxiv.11871402
Spector AA, Kim H-Y (2015). Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1851 (4): 356-365.
Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J et al. (2020). QMEANDisCo—distance constraints applied on model quality estimation. Bioinformatics 36: 1765-1771.
Tallei TE, Tumilaar SG, Niode NJ, Fatimawali F, Kepel BJ et al. (2020). Potential of plant bioactive compounds as SARSCoV-2 main protease (Mpro) and spike (S) glycoprotein inhibitors: a molecular docking study. Preprints. doi: 10.20944/ preprints202004.0102.v2
Thuy BTP, My TTA, Hai NTT, Hieu LT, Hoa TT et al. (2020). Investigation into SARS-CoV-2 resistance of compounds in garlic essential oil. ACS Omega 5 (14): 8312-8320.
Wang C, Horby PW, Hayden FG, Gao GF (2020). A novel coronavirus outbreak of global health concern. The Lancet 395: 470-473.
Wilson S, Greer B, Hooper J, Zijlstra A, Walker B et al. (2005). The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochemical Journal 388: 967- 972.
Xiang Z (2006). Advances in homology protein structure modeling. Current Protein and Peptide Science 7 (3): 217-227. Zar J (1996). Biostatistical analysis. London, UK: Prentice–Hall International Inc.
Zhu N, Zhang D, Wang W, Li X, Yang B et al. (2020). China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine 382: 727-733.