Determination of the interaction between the receptor binding domain of 2019-nCoV
spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms
of some flavonols

kilic, Ibrahim Halil; SIHOGLU TEPE, Arzuhan; TEPE, Bektas; Sarikurkcu, Cengiz; Netz, Paulo; Istifli, Erman Salih

doi:10.3906/biy-2104-51

Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols

Erman Salih İSTİFLİ, (Çukurova Üniversitesi, Fen Edebiyat Fakültesi, Biyoloji Bölümü, Adana, Türkiye)

Arzuhan SIHOGLU TEPE, (Kilis 7 Aralık Üniversitesi, Sağlık Hizmetleri Meslek Yüksekokulu, Eczacılık Hizmetleri Anabilim Dalı, Kilis, Türkiye)

Paulo A. NETZ, (Theoretical Chemistry Group, Institute of Chemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil)

Cengiz SARIKÜRKÇÜ, (Afyonkarahisar Sağlık Bilimleri Üniversitesi, Eczacılık Fakültesi, Analitik Kimya Anabilim Dalı, Afyonkarahisar, Türkiye)

İbrahim Halil KILIÇ, (Gaziantep Üniversitesi, Fen Edebiyat Fakültesi, Biyoloji Bölümü, Gaziantep, Türkiye)

Bektaş TEPE (Kilis 7 Aralik Üniversitesi, Fen Edebiyat Fakültesi, Moleküler Biyoloji ve Genetik Bölümü, Kilis, Türkiye)

Turkish Journal of Biology

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Yıl: 2021 Cilt: 45 Sayı: 4 Sayfa Aralığı: 484 - 502 Metin Dili: İngilizce DOI: 10.3906/biy-2104-51 İndeks Tarihi: 20-06-2022

Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols

Öz:

The novel coronavirus (COVID-19, SARS-CoV-2) is a rapidly spreading disease with a high mortality. In this research, the interactions between specific flavonols and the 2019-nCoV receptor binding domain (RBD), transmembrane protease, serine 2 (TMPRSS2), and cathepsins (CatB and CatL) were analyzed. According to the relative binding capacity index (RBCI) calculated based on the free energy of binding and calculated inhibition constants, it was determined that robinin (ROB) and gossypetin (GOS) were the most effective flavonols on all targets. While the binding free energy of ROB with the spike glycoprotein RBD, TMPRSS2, CatB, and CatL were –5.02, –7.57, –10.10, and –6.11 kcal/mol, the values for GOS were –4.67, –5.24, –8.31, and –6.76, respectively. Furthermore, both compounds maintained their stability for at least 170 ns on respective targets in molecular dynamics simulations. The molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations also corroborated these data. Considering Lipinski’s rule of five, ROB and GOS exhibited 3 (MW>500, N or O>10, NH or OH>5), and 1 (NH or OH>5) violations, respectively. Neither ROB nor GOS showed AMES toxicity or hepatotoxicity. The LD50 of these compounds in rats were 2.482 and 2.527 mol/kg, respectively. Therefore, we conclude that these compounds could be considered as alternative therapeutic agents in the treatment of COVID-19. However, the possible inhibitory effects of these compounds on cytochromes (CYPs) should be verified by in vitro or in vivo tests and their adverse effects on cellular energy metabolism should be minimized by performing molecular modifications if necessary.

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Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

Abd El-Mordy FM, El-Hamouly MM, Ibrahim MT, Abd El-Rheem G, Aly OM et al. (2020). Inhibition of SARS-CoV-2 main protease by phenolic compounds from Manilkara hexandra (Roxb.) Dubard assisted by metabolite profiling and in silico virtual screening. RSC Advances 10: 32148-32155.
Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC et al. (2015). GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1-2: 19-25.
Adejoro IA, Babatunde DD, Tolufashe GF (2020). Molecular docking and dynamic simulations of some medicinal plants compounds against SARS-CoV-2: an in silico study. Journal of Taibah University for Science 14: 1563-1570.
Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF (2020). The proximal origin of SARS-CoV-2. Nature Medicine 26: 450- 452.
Arokiyaraj S, Stalin A, Kannan BS, Shin H (2020). Geranii Herba as a potential inhibitor of SARS-CoV-2 main 3CLpro, spike RBD, and regulation of unfolded protein response: an in silico approach. Antibiotics 9: 863.
Arora S, Lohiya G, Moharir K, Shah S, Yende S (2020). Identification of potential flavonoid inhibitors of the SARS-CoV-2 main protease 6YNQ: a molecular docking study. Digital Chinese Medicine 3: 239-248.
Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001). Electrostatics of nanosystems: application to microtubules and the ribosome. Proceedings of the National Academy of Sciences 98: 10037-10041.
Batool F, Mughal EU, Zia K, Sadiq A, Naeem N et al. (2020). Synthetic flavonoids as potential antiviral agents against SARSCoV-2 main protease. Journal of Biomolecular Structure and Dynamics (In press). doi: 10.1080/07391102.2020.1850359
Camacho C, Coulouris G, Avagyan V, Ma N, Papadopoulos J et al. (2009). BLAST+: architecture and applications. BMC Bioinformatics 10: 421.
Cannalire R, Stefanelli I, Cerchia C, Beccari AR, Pelliccia S et al. (2020). SARS-CoV-2 entry inhibitors: small molecules and peptides targeting virus or host cells. International Journal of Molecular Sciences 21: 5707.
Cataneo AHD, Kuczera D, Koishi AC, Zanluca C, Silveira GF et al. (2019). The citrus flavonoid naringenin impairs the in vitro infection of human cells by Zika virus. Scientific Reports 9: 16348.
Chan-Yeung M, Xu RH (2003). SARS: epidemiology. Respirology 8: S9-S14.
Chan JF-W, Kok K-H, Zhu Z, Chu H, To KK-Wet al. (2020). Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerging Microbes & Infections 9: 221- 236.
Chen M, Chen XX, Song X, Muhammad A, Jia RY et al. (2019). The immune-adjuvant activity and the mechanism of resveratrol on pseudorabies virus vaccine in a mouse model. International Immunopharmacology 76: 105876.
Chen Y, Li P, Su SJ, Chen M, He J et al. (2019). Synthesis and antibacterial and antiviral activities of myricetin derivatives containing a 1,2,4-triazole Schiff base. RSC Advances 9: 23045-23052.
Cherrak SA, Merzouk H, Mokhtari-Soulimane N (2020). Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: a molecular docking and simulation studies. Plos One 15: e0240653.
Colovos C, Yeates TO (1993). Verification of protein structures: patterns of nonbonded atomic interactions. Protein Science 2: 1511-1519.
Dai WW, Bi JP, Li F, Wang S, Huang XY et al. (2019). Antiviral efficacy of flavonoids against enterovirus 71 infection in vitro and in newborn mice. Viruses 11: 625.
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). SwissTarget prediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research 47: W357-W364.
Darden T, York D, Pedersen L (1993). Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. The Journal of Chemical Physics 98: 10089-10092.
Dávalos A, Castilla P, Gómez-Cordovés C, Bartolomé B (2006). Quercetin is bioavailable from a single ingestion of grape juice. International Journal of Food Sciences and Nutrition 57: 391-398.
De Andrade J, Gonçalves PFB, Netz PA (2021). Why does the novel coronavirus spike protein interact so strongly with the human ACE2? A thermodynamic answer. ChemBioChem 22: 865- 875. doi.org/10.1002/cbic.202000455
Jesús-González LAD, Osuna-Ramos JF, Reyes-Ruiz JM, et al. (2020). Flavonoids and nucleotide analogs show high affinity for viral proteins of SARS-CoV-2 by in silico analysis: new candidates for the treatment of COVID-19. Research Square (Preprint). doi: 10.21203/rs.3.rs-67272/v1.
Del Barrio G, Spengler I, Garcia T, Roque A, Alvarez AL et al. (2011). Antiviral activity of Ageratina havanensis and major chemical compounds from the most active fraction. Revista Brasileira De Farmacognosia 21: 915-920.
Delaney JS (2004). ESOL: estimating aqueous solubility directly from molecular structure. Journal of Chemical Information and Computer Sciences 44: 1000-1005.
Duan CJ, Xian L, Zhao GC, Feng Y, Pang Het al. (2009). Isolation and partial characterization of novel genes encoding acidic cellulases from metagenomes of buffalo rumens. Journal of Applied Microbiology 107: 245-256.
Dwivedi VD, Bharadwaj S, Afroz S, Khan N, Ansari MA et al. (2020). Anti-dengue infectivity evaluation of bioflavonoid from Azadirachta indica by dengue virus serine protease inhibition. Journal of Biomolecular Structure & Dynamics. doi: 10.1080/0 7391102.07392020.01734485
Ebada SS, Al-Jawabri NA, Youssef FS, El-Kashef DH, Knedel T-O et al. (2020). Anti-inflammatory, antiallergic and COVID-19 protease inhibitory activities of phytochemicals from the Jordanian hawksbeard: identification, structure–activity relationships, molecular modeling and impact on its folk medicinal uses. RSC Advances 10: 38128-38141.
Essmann U, Perera L, Berkowitz ML, Darden T, Lee H et al. (1995). A smooth particle mesh Ewald method. The Journal of Chemical Physics 103: 8577-8593.
Fischer A, Sellner M, Neranjan S, Smieško M, Lill MA (2020). Potential inhibitors for novel coronavirus protease identified by virtual screening of 606 million compounds. International Journal of Molecular Sciences 21: 3626.
Genheden S, Ryde U (2015). The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opinion on Drug Discovery 10: 449-461.
Giguet-Valard A-G, Raguette K, Morin S, Bellance R, Ravin JS (2020). Gossypetin derivatives are also putative inhibitors of SARSCoV-2: results of a computational study. Journal of Biomedical Research & Environmental Sciences 1: 201-212.
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.
Guex N, Peitsch MC, Schwede T (2009). Automated comparative protein structure modeling with SWISS‐MODEL and Swiss‐ PdbViewer: a historical perspective. Electrophoresis 30: S162-S173.
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: 2048-2054.
Hashem HE (2020). In silico approach of some selected honey constituents as SARS-CoV-2 main protease (COVID-19) inhibitors. Eurasian Journal of Medicine and Oncology 4: 196- 200.
Hiremath S, Kumar HV, Nandan M, Mantesh M et al. (2021). In silico docking analysis revealed the potential of phytochemicals present in Phyllanthus amarus and Andrographis paniculata, used in Ayurveda medicine in inhibiting SARS-CoV-2. 3 Biotechnology 11: 1-18.
Homeyer N, Gohlke H (2012). Free energy calculations by the molecular mechanics Poisson-Boltzmann surface area method. Molecular Informatics 31: 114-122.
Hoover WG (1985). Canonical dynamics: equilibrium phase-space distributions. Physical Review A 31: 1695-1697.
Hu X, Cai X, Song X, Li C, Zhao Jet al. (2020). Possible SARScoronavirus 2 inhibitor revealed by simulated molecular docking to viral main protease and host toll-like receptor. Future Virology 15: 359-368.
Huang C, Wang Y, Li X, Ren L, Zhao Jet al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395: 497-506.
Istifli ES, Netz PA, Sihoglu Tepe A, Husunet MT, Sarikurkcu C et al. (2020). In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties. Journal of Biomolecular Structure and Dynamics 1-15. (In press). doi: 10.1080/07391102.2020.1840444
Istifli ES, Sihoglu Tepe A, Sarikurkcu C, Tepe B (2020). Interaction of certain monoterpenoid hydrocarbons with the receptorbinding domain of 2019 novel coronavirus (2019-nCoV), transmembrane serin protease 2 (TMPRSS2), cathepsin B, and cathepsin L (CatB/L) and their pharmacokinetic properties. Turkish Journal of Biology 44: 242-264.
Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M et al. (2019). TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. Journal of Virology 93.
Jain AS, Sushma P, Dharmashekar C, Beelagi MS, Prasad SK et al. (2021). In silico evaluation of flavonoids as effective antiviral agents on the spike glycoprotein of SARS-CoV-2. Saudi Journal of Biological Sciences 28: 1040-1051.
Jakalian A, Jack DB, Bayly CI (2002). Fast, efficient generation of highquality atomic charges. AM1-BCC model: II. Parameterization and validation. Journal of Computational Chemistry 23: 1623- 1641.
Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983). Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics 79: 926-935.
Joshi R, Jagdale S, Bansode S, Shankar SS, Tellis M et al. (2020). Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. Journal of Biomolecular Structure and Dynamics. doi: 10.1080/07391102.2020.1760137
Kandeel M, Kitade Y, Almubarak A (2020). Repurposing FDAapproved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase. PeerJ 8: e10480.
Kawase M, Shirato K, Van der Hoek L, Taguchi F, Matsuyama S (2012). Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. Journal of Virology 86: 6537-6545.
Keramagi AR, Skariyachan S (2018). Prediction of binding potential of natural leads against the prioritized drug targets of chikungunya and dengue viruses by computational screening. 3 Biotech 8 (6): 14.
Kollman PA, Massova I, Reyes C, Kuhn B, Huo S et al. (2000). Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Accounts of Chemical Research 33: 889-897.
Kousar K, Majeed A, Yasmin F, Hussain W, Rasool N (2020). Phytochemicals from selective plants have promising potential against SARS-CoV-2: investigation and corroboration through molecular docking, MD simulations, and quantum computations. BioMed Research International 2020: 6237160.
Kumari R, Kumar R, Lynn A (2014). g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. Journal of Chemical Information and Modeling 54: 1951-1962.
Kumari R, Kumar R. Open Source Drug Discovery C, Lynn A (2014). g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations. Journal of Chemical Information and Modeling 54: 1951-1962.
Lan J, Ge J, Yu J, Shan S, Zhou Het al. (2020). Structure of the SARSCoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581: 215-220.
Laskar MA, Begam M, Dutta Choudhury M. In silico screening of some antiviral phytochemicals as drug leads against Covid-19. ChemRxiv Preprint 2020. doi: 10.26434/chemrxiv.12478568.v
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.
LeCher JC, Diep N, Krug PW, Hilliard JK (2019). Genistein has antiviral activity against herpes B virus and acts synergistically with antiviral treatments to reduce effective dose. Viruses 11: E499.
Leung EL, Pan HD, Huang YF, Fan XX, Wang WY et al. (2020). The Scientific Foundation of Chinese Herbal Medicine against COVID-19. Engineering (Beijing) 6: 1099-1107.
Ling LJ, Lu Y, Zhang YY, Zhu HY, Tu P et al. (2020). Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and toll-like receptor signaling. Phytomedicine 67: 153150.
Lopes BRP, Da Costa MF, Ribeiro AG, Da Silva TF, Lima CS et al. (2020). Quercetin pentaacetate inhibits in vitro human respiratory syncytial virus adhesion. Virus Research 276: 197805.
Memish ZA, Perlman S, Van Kerkhove MD, Zumla A (2020). Middle East respiratory syndrome. The Lancet 395: 1063-1077.
Mohd A, Zainal N, Tan KK, AbuBakar S (2019). Resveratrol affects Zika virus replication in vitro. Scientific Reports 9: 14336.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK et al. (2009). AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30: 2785-2791.
Morris GM, Lim-Wilby M (2008). Molecular docking. In: Kukol A (Ed.) Molecular Modeling of Proteins. Springer, Switzerland, pp. 365-382.
Nagai E, Iwai M, Koketsu R, Okuno Y, Suzuki Y et al. (2019). Antiinfluenza virus activity of adlay tea components. Plant Foods for Human Nutrition 74: 538-543.
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: 425-433.
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T et al. (2011). Open Babel: an open chemical toolbox. Journal of Cheminformatics 3: 33.
Oladele JO, Oyeleke OM, Oladele OT, Olowookere BD, Oso BJ et al. (2020). Kolaviron (Kolaflavanone), apigenin, fisetin as potential Coronavirus inhibitors: in silico investigation. Research Square. doi: 10.21203/rs.3.rs-51350/v1
Omotuyi IO, Nash O, Ajiboye OB, Iwegbulam CG, Oyinloye EB et al. (2020). Atomistic simulation reveals structural mechanisms underlying D614G spike glycoprotein-enhanced fitness inSARS-COV-2. Journal of Computational Chemistry 41: 2158-2161.
Parrinello M, Rahman A (1981). Polymorphic transitions in single crystals: a new molecular dynamics method. Journal of Applied Physics 52: 7182-7190.
Parvez MK, Rehman MT, Alam P, Al-Dosari MS, Alqasoumi SI et al. (2019). Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: cell culture and molecular docking study. Saudi Pharmacological Journal 27: 389-400.
Patel R, Vanzara A, Patel N, Vasava A, Patil S et al. (2020). Discovery of fungal metabolites bergenin, quercitrin and dihydroartemisinin as potential inhibitors against main protease of SARS-CoV-2. Biological and Medicinal Chemistry (preprint).
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.
Perez-Vizcaino F, Duarte J (2010). Flavonols and cardiovascular disease. Molecular Aspects of Medicine 31: 478-494.
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.
Puttaswamy H, Gowtham HG, Ojha MD, Yadav A, Choudhir G et al. (2020). In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis. Scientific Reports 10: 1-24.
Raj U, Varadwaj PK (2016). Flavonoids as multi-target inhibitors for proteins associated with ebola virus: in silico discovery using virtual screening and molecular docking studies. Interdisciplinary Sciences-Computational Life Sciences 8: 132- 141.
Remmert M, Biegert A, Hauser A, Söding J (2012). HHblits: lightning-fast iterative protein sequence searching by HMMHMM alignment. Nature Methods 9: 173-175.
Richman DD, Whitley RJ, Hayden FG (2016). Clinical virology, 4th ed. John Wiley & Sons.
Ritta M, Marengo A, Civra A, Lembo D, Cagliero C et al. (2020). Antiviral activity of a Arisaema tortuosum leaf extract and some of its constituents against herpes simplex virus type 2. Planta Medica 86: 267-275.
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: 237-286.
Shirato K, Kanou K, Kawase M, Matsuyama S (2017). Clinical isolates of human coronavirus 229E bypass the endosome for cell entry. Journal of Virology 91.
Shirato K, Kawase M, Matsuyama S (2018). Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 517: 9-15.
Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL et al. (2005). Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proceedings of the National Academy of Sciences 102: 11876-11881.
Singhal T (2020). A review of coronavirus disease-2019 (COVID-19). Indian Journal of Pediatrics 87: 281-286.
Sochocka M, Sobczynski M, Ochnik M, Zwolinska K, Leszek J (2019). Hampering herpesviruses HHV-1 and HHV-2 infection by extract of Ginkgo biloba (EGb) and its phytochemical constituents. Frontiers in Microbiology 10: 2367.
Somadi G, Sivan SK (2020). Identification of therapeutic target in S2 domain of SARS nCov-2 spike glycoprotein: key to design and discover drug candidates for inhibition of viral entry into host cell. Journal of Theoretical and Computational Chemistry 19: 2050028.
Sousa da Silva AW, Vranken WF (2012). ACPYPE - AnteChamber PYthon Parser interfacE. BMC Research Notes 5: 367.
Srivastava S, Shree P, Tripathi YB (2017). Active phytochemicals of Pueraria tuberosa for DPP-IV inhibition: in silico and experimental approach. Journal of Diabetes & Metabolic Disorders 16: 46.
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.
Sun H, Duan L, Chen F, Liu H, Wang Z et al. (2018). Assessing the performance of MM/PBSA and MM/GBSA methods. 7. Entropy effects on the performance of end-point binding free energy calculation approaches. Physical Chemistry Chemical Physics 20: 14450-14460.
Swargiary A, Mahmud S, Saleh MA (2020). Screening of phytochemicals as potent inhibitor of 3-chymotrypsin and papain-like proteases of SARS-CoV2: an in silico approach to combat COVID-19. Journal of Biomolecular Structure and Dynamics. doi: 10.1080/07391102.2020.1835729
Tang X, Zhang C, Chen M, Xue YN, Liu TT et al. (2020). Synthesis and antiviral activity of novel myricetin derivatives containing ferulic acid amide scaffolds. New Journal of Chemistry 44: 2374-2379.
Teli DM, Shah MB, Chhabria MT (2020). In silico screening of natural compounds as potential inhibitors of SARS-CoV-2 main protease and spike receptor-binding domain bound with ACE2 COVID-19 target proteins. Frontiers in Molecular Biosciences 7: 429.
Trujillo-Correa AI, Quintero-Gil DC, Diaz-Castillo F, Quinones W, Robledo SM et al. (2019). In vitro and in silico anti-dengue activity of compounds obtained from Psidium guajava through bioprospecting. BMC Complementary and Alternative Medicine 19: 298.
Tsiklauri L, Svik K, Chrastina M, Ponist S, Drafi F et al. (2021). Bioflavonoid robinin from Astragalus falcatus Lam. mildly improves the effect of metothrexate in rats with adjuvant arthritis. Nutrients 13: 1268.
Vazquez-Calvo A, De Oya NJ, Martin-Acebes MA, GarciaMoruno E, Saiz JC (2017). Antiviral properties of the natural polyphenols delphinidin and epigallocatechin gallate against the flaviviruses West Nile virus, Zika virus, and Dengue virus. Frontiers in Microbiology 8: 1314.
Vijayakumar BG, Ramesh D, Joji A, Kannan T (2020). In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. European Journal of Pharmacology 886: 173448.
Vistoli G, Pedretti A, Testa B (2008). Assessing drug-likeness--what are we missing? Drug Discovery Today 13: 285-294.
Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004). Development and testing of a general amber force field. Journal of Computational Chemistry 25: 1157-1174.
Wang R, Zhang X, Irwin DM, Shen Y (2020). Emergence of SARSlike coronavirus poses new challenge in China. Journal of Infection 80: 350-371.
Wang Y, Liu M, Gao J (2020). Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proceedings of the National Academy of Sciences 117: 13967-13974.
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.
Woo H, Park SJ, Choi YK, Park T, Tanveer M et al. (2020). Developing a fully glycosylated full-length SARS-CoV-2 spike protein model in a viral membrane. The Journal of Physical Chemistry B.
Zakaryan H, Arabyan E, Oo A, Zandi K (2017). Flavonoids: promising natural compounds against viral infections. Archives of Virology 162: 2539-2551.
Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion Jr R et al. (2015). Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Research 116: 76-84.

APA	Istifli E, SIHOGLU TEPE A, Netz P, Sarikurkcu C, kilic I, TEPE B (2021). Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. , 484 - 502. 10.3906/biy-2104-51
Chicago	Istifli Erman Salih,SIHOGLU TEPE Arzuhan,Netz Paulo,Sarikurkcu Cengiz,kilic Ibrahim Halil,TEPE Bektas Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. (2021): 484 - 502. 10.3906/biy-2104-51
MLA	Istifli Erman Salih,SIHOGLU TEPE Arzuhan,Netz Paulo,Sarikurkcu Cengiz,kilic Ibrahim Halil,TEPE Bektas Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. , 2021, ss.484 - 502. 10.3906/biy-2104-51
AMA	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. . 2021; 484 - 502. 10.3906/biy-2104-51
Vancouver	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. . 2021; 484 - 502. 10.3906/biy-2104-51
IEEE	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B "Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols." , ss.484 - 502, 2021. 10.3906/biy-2104-51
ISNAD	Istifli, Erman Salih vd. "Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols". (2021), 484-502. https://doi.org/10.3906/biy-2104-51

APA	Istifli E, SIHOGLU TEPE A, Netz P, Sarikurkcu C, kilic I, TEPE B (2021). Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. Turkish Journal of Biology, 45(4), 484 - 502. 10.3906/biy-2104-51
Chicago	Istifli Erman Salih,SIHOGLU TEPE Arzuhan,Netz Paulo,Sarikurkcu Cengiz,kilic Ibrahim Halil,TEPE Bektas Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. Turkish Journal of Biology 45, no.4 (2021): 484 - 502. 10.3906/biy-2104-51
MLA	Istifli Erman Salih,SIHOGLU TEPE Arzuhan,Netz Paulo,Sarikurkcu Cengiz,kilic Ibrahim Halil,TEPE Bektas Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. Turkish Journal of Biology, vol.45, no.4, 2021, ss.484 - 502. 10.3906/biy-2104-51
AMA	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. Turkish Journal of Biology. 2021; 45(4): 484 - 502. 10.3906/biy-2104-51
Vancouver	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols. Turkish Journal of Biology. 2021; 45(4): 484 - 502. 10.3906/biy-2104-51
IEEE	Istifli E,SIHOGLU TEPE A,Netz P,Sarikurkcu C,kilic I,TEPE B "Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols." Turkish Journal of Biology, 45, ss.484 - 502, 2021. 10.3906/biy-2104-51
ISNAD	Istifli, Erman Salih vd. "Determination of the interaction between the receptor binding domain of 2019-nCoV spike protein, TMPRSS2, cathepsin B and cathepsin L, and glycosidic and aglycon forms of some flavonols". Turkish Journal of Biology 45/4 (2021), 484-502. https://doi.org/10.3906/biy-2104-51