Ebrar Nur ŞAHİN, Abdullah KARANFİL, Ertan ŞAHİN, Latif KELEBEKLİ

Halojenli Bisiklo[4.2.0] İnositollerin SARS-CoV-2 Proteinleri ile Moleküler Doking Çalışmaları

Siklik sülfat, SARS-CoV-2'nin kenetlenmiş proteinlerinin bağlanma bölgelerine iyi uyum sağlayabilen öncü bileşiktir. Siklik Sülfat, SARS-CoV-2'nin 6lu7, 6zb5 ve 6vww proteinleri için sırasıyla -7.33, -7.29 ve -7.29 kcal mol-1 'lük bağlanma enerjileriyle çok güçlü moleküler etkileşimler gösterdi. Ayrıca asetat, SARS-CoV-2'nin 6lu7 proteini için -7.45 kcal mol-1 ile çok güçlü moleküler etkileşimler gösterdi. Bu nedenle sonuçlarımıza göre siklik sülfat ve asetat, COVID-19 tedavisi için umut verici bir ilaç adayı olarak araştırılmalıdır.

Anahtar Kelimeler:

moleküler doking, RdRp, Mpro, SGp, inositol

Molecular Docking Studies of Halogenated Bicyclo[4.2.0] Inositols with SARS-CoV-2 Proteins

Cyclic sulfate is the precursor compound that can adapt well to the binding sites of the docked proteins of SARS-CoV-2. Cyclic sulfate showed very strong molecular interactions for the 6lu7, 6zb5, and 6vww proteins of SARS-CoV-2, with binding energies of -7.33, -7.29, and -7.29 kcal mol-1, respectively. Besides, acetate showed very strong molecular interactions with -7.45 kcal mol-1 for the 6lu7 protein of SARS-CoV-2. Therefore, according to our results, cyclic sulfate and acetate should be investigated as promising drug candidates for the treatment of COVID-19.

Keywords:

molecular docking, RdRp, Mpro, SGp, inositol,

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Adam, W., & Balci, M. (1980). Cyclic polyepoxides: Synthetic, structural and biological aspects. Tetrahedron, 36(7), 833-858. https://doi.org/10.1016/0040-4020(80)80034-2
Aksu, A., Akincioglu, H., Gulcin, İ., & Kelebekli, L. (2021). Concise syntheses and some biological activities of DL‐2,5‐di‐O‐methyl‐chiro‐inositol, DL‐1,4‐di‐O‐methyl‐scyllo‐inositol, and DL‐1,6‐dibromo‐1,6‐dideoxy‐2,5‐di‐O‐methyl‐chiroinositol. Archiv der Pharmazie, 354, e2000254. https://doi.org/10.1002/ardp.202000254
Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., Baric, R. S., & Denison, M. R. (2018). Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio, 9(2), e00221-18. https://doi.org/10.1128/mBio.00221-18
Agrawal, U., Raju, R., & Udwadia, Z. F. (2020). Favipiravir: A new and emerging antiviral option in COVID-19. Medical Journal Armed Forces India, 76(4), 370–376. https://doi.org/10.1016/j.mjafi.2020.08.004
Allen, C. N. S., Arjona, S. P., Santerre, M., & Sawaya, B. E. (2020). Potential use of RNA-dependent RNA polymerase (RdRp) inhibitors against SARS-CoV2 infection. All Life, 13(1), 608–614. https://doi.org/10.1080/26895293.2020.1835741
Arouche, T. D. S., Martins, A. Y., Ramalho, T. C., Júnior, R. N. C., Costa, F. L. P., Filho, T. S. A., & Neto, A. M. J. C. (2021). Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases. Journal of Nanoscience and Nanotechnology, 21(4), 2075-2089. https://doi.org/10.1166/jnn.2021.19029
Bizzarri, M., Laganà, A. S., Aragona, D., & Unfer, V. (2020). Inositol and pulmonary function. Could myo-inositol treatment downregulate inflammation and cytokine release syndrome in SARS-CoV-2? European Review for Medical and Pharmacological Sciences, 24(6), 3426-3432.https://doi.org/10.26355/eurrev_202003_20715
Brown, A. J., Won, J. J., Graham, R. L., Dinnon, K. H., Sims, A. C., Feng, J. Y., Cihlar, T., Denison, M. R., Baric, R. S., & Sheahan, T. P. (2019). Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Research, 169, 104541. https://doi.org/10.1016/j.antiviral.2019.104541
de Wit, E., Feldmann, F., Cronin, J., Jordan, R., Okumura, A., Thomas, T., Scott, D., Cihlar, T., & Feldmann, H. (2020). Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.Proceedings of the National Academy of Sciences, 117(12), 6771-6776. https://doi.org/10.1073/pnas.1922083117
de Wit, E., Rasmussen, A. L., Falzarano, D., Bushmaker, T., Feldmann, F., Brining, D. L., Fischer, E. R., Martellaro, C., Okumura, A., Chang, J., Scott, D., Benecke, A. G., Katze, M. G., Feldmann, H., &Munster,V. J. (2013). Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques.Proceedings of the National Academy of Sciences, 110(41), 16598-16603. https://doi.org/10.1073/pnas.1310744110
Espinola, M. S. B., Bertelli, M., Bizzarri, M., Unfer, V., Laganà, A. S., Visconti, B., & Aragona, C. (2021). Inositol and vitamin D may naturally protect human reproduction and women undergoing assisted reproduction from Covid-19 risk. Journal of Reproductive Immunology, 144, 103271. https://doi.org/10.1016/j.jri.2021.103271
Food, U., & Administration, D. (2020). Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Veklury® (remdesivir). https://www.fda.gov/media/137566/download Furuta, Y., Takahashi, K., Fukuda, Y., Kuno, M., Kamiyama, T., Kozaki, K., Nomura, N., Egawa, H., Minami, S., Watanabe, Y., Narita, H., & Shiraki, K. (2002). In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrobial Agents and Chemotherapy, 46(4), 977–981. https://doi.org/10.1128/AAC.46.4.977-981.2002
Kamenov, Z., & Gateva, A. (2020). Inositols in PCOS. Molecules, 25(23), 5566. https://doi.org/10.3390/molecules25235566
Karanfil, A., Şahin, E., & Kelebekli, L. (2020). Synthesis of novel tetrols from syn-bisepoxide: Preparation of halogenated bicyclo[4.2.0] inositols. Tetrahedron, 76(11), 131000. https://doi.org/10.1016/j.tet.2020.131000
Kelebekli, L., Kara, Y., & Balci, M. (2005). Stereospecific synthesis of a new class of compounds: bis-homoconduritol-A, -D, and-F. Carbohydrate Research, 340(12), 1940-1948. https://doi.org/10.1016/j.carres.2005.05.021
Kelebekli, L., & Kaplan, D. (2017). Stereospecific synthesis of novel methyl-substituted mono- and dimethoxy Conduritols. Tetrahedron, 73, 8-13. http://dx.doi.org/10.1016/j.tet.2016.11.042
Kelebekli, L., & Atlı, İ. (2019). Stereoselective synthesis of a new methyl-substituted inositol Derivative, Tetrahedron, 75, 130531. https://doi.org/10.1016/j.tet.2019.130531
Lagana, A. S., Unfer, V., Garzon, S., & Mariano Bizzarri, M. (2020). Role of inositol to improve surfactant functions and reduce IL-6 levels: A potential adjuvant strategy for SARS-CoV-2 pneumonia? Medical Hypotheses, 144, 110262. https://doi.org/10.1016/j.mehy.2020.110262
López, M. D., Cobo, J., & Nogueras, M. (2008). Building Bicyclic Polyhydroxylated Alkaloids: An Overview from 1995 to the Present. Current Organic Chemistry, 12(9), 718-750. https://doi.org/10.2174/138527208784567197
Goodsell D. S, Morris G. M, Olson A. J. (1996). Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit, 9(1), 1-5. https://doi.org/10.1002/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6
Rafi, M. O., Bhattacharje, G., Al-Khafaji, K., Taskin-Tok, T., Alfasane, M. A., Das, A. K., Parvez, M. A. K., & Rahman, M. S. (2020). Combination of QSAR, molecular docking, molecular dynamic simulation and MM-PBSA: analogues of lopinavir and favipiravir as potential drug candidates against COVID-19. Journal of Biomolecular Structure and Dynamics, 30, 1-20. https://doi.org/10.1080/07391102.2020.1850355
Rubin, D., Chan-Tack, K., Farley, J., & Sherwat, A. (2020). FDA Approval of Remdesivir — A Step in the Right Direction. New England Journal of Medicine, 383, 2598–2600. https://doi.org/10.1056/NEJMp2032369
Sheahan, T. P., Sims, A. C., Graham, R. L., Menachery, V. D., Gralinski, L. E., Case, J. B., Leist, S. R., Pyrc, K., Feng, J. Y., Trantcheva, I., Bannister, R., Park, Y., Babusis, D., Clarke, M. O., Mackman, R.L., Spahn, J. E., Palmiotti, C. A., Siegel, D., Ray, A. S., & Baric, R.S. (2017). Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine, 9(396), eaal3653. https://doi.org/10.1126/scitranslmed.aal3653
Sun, Y., Zhang, G., Hawkes, C. A., Shaw, J. E., McLaurin, J. A., & Nitz, M. (2008). Synthesis of scyllo- inositol derivatives and their effects on amyloid beta peptide aggregation. Bioorganic & Medicinal Chemistry, 16(15), 7177-7184. https://doi.org/10.1016/j.bmc.2008.06.045
Şahin, E. N., Karanfil, A., Ayvaz, M. Ç., Şahin, E., & Kelebekli, L. (2022). Structural analysis of halogenated bicyclo[4.2.0] inositols, biological activities and molecular docking studies. Journal of Molecular Structure, 1248, 131357. https://doi.org/10.1016/J.MOLSTRUC.2021.131357
Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30, 269–271. https://doi.org/10.1038/s41422-020-0282-0
Wang, N., Hang, L-H., & Ye, X-S. (2010). A new synthetic access to bicyclic polyhydroxylated alkaloid analogues from pyranosides. Organic & Biomolecular Chemistry, 11(8), 2639-2649. https://doi.org/10.1039/B923180C
Wu, R., Wang, L., Kuo, H-C. D., Shannar, A., Peter, R., Chou, P. J., Li, S., Hudlikar, R., Liu, X., Liu, Z., Poiani, G. J., Amorosa, L., Brunetti, L., & Kong, A-N. (2020). An Update on Current Therapeutic Drugs Treating COVID-19. Current Pharmacology Reports, 6, 56-70. https://doi.org/10.1007/s40495-020-00216-7
Zanardi, F., Battistini, L., Marzocchi, L., Acquotti, D., Rassu, G., Pinna, L., Auzzas, L., Zambrano, V., & Casiraghi, G. (2002). Synthesis of a Small Repertoire of Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses. European Journal of Organic Chemistry, 2002(12), 1956-1964. https://doi.org/10.1002/1099-0690(200206)2002:12<1956::AID-EJOC1956>3.0.CO;2-Y