In silico study and structure-activity relations of glucose-bound coumarin derivatives against the NSP12 protein of SARS-CoV-2

Year 2021, Volume: 1 Issue: 1, 29 - 37, 12.11.2021

Esra Çelik Mücahit Özdemir Bahattin Yalçın Baybars Köksoy

Abstract

In this study, designs of antiviral drug candidates that may be effective against SARS-CoV-2 virus were performed. Molecular docking was used to explore the effect of coumarin and its derivatives, which have antiviral action, on RNA polymerase NSP12, one of the key proteins of the coronavirus. The sugar group on coumarins was selected to increase hydrophilicity, and the amide groups were diversified to investigate selectivity. Coumarins containing 3-(p-phenylamidomorpholine), 3-(p-phenylamidopiperazine), and 3-(p-phenylamidopiperidine) groups had the best docking scores, with binding affinities of -10.1 kcal/mol, -10.1 kcal/mol, and -10.0 kcal/mol, respectively. The pharmacokinetic and toxicokinetic properties of compounds were estimated close to reality using various databases, and their values were close to the target values needed for a compound to become a drug. This study is also thought to give insight to scientists working for the design of SARS-CoV-2 antiviral drugs in terms of the structure activity relationship between coumarin and its functional groups.

Keywords

SARS-CoV-2, COVID-19, Coronavirus, Coumarin, Drug design, Molecular docking.

SARS-CoV-2'nin NSP12 proteinine karşı glukoza bağlı kumarin türevlerinin in silico çalışması ve yapı-aktivite ilişkileri

Abstract

Bu çalışmada SARS-CoV-2 virüsüne karşı etkili olabilecek antiviral ilaç adaylarının tasarımları yapılmıştır. Moleküler yerleştirme, antiviral etkiye sahip kumarin ve türevlerinin, koronavirüsün temel proteinlerinden biri olan RNA polimeraz NSP12 üzerindeki etkisini araştırmak için kullanıldı. Kumarinlerdeki şeker grubu, hidrofilisiteyi arttırmak için seçilmiş ve seçiciliği araştırmak için amid grupları çeşitlendirilmiştir. 3-(p-fenilamidomorfolin), 3-(p-fenilamidopiperazin) ve 3-(p-fenilamidopiperidin) gruplarını içeren kumarinler, sırasıyla -10.1 kcal/mol, -10.1 kcal/mol, and -10.0 kcal/mol bağlanma afiniteleriyle en iyi yerleştirme puanlarına sahipti. Bileşiklerin farmakokinetik ve toksikokinetik özellikleri, çeşitli veri tabanları kullanılarak gerçeğe yakın olarak tahmin edildi ve değerleri, bir bileşiğin ilaca dönüşmesi için gereken hedef değerlere yakındı. Bu çalışmanın ayrıca SARS-CoV-2 antiviral ilaçların tasarımı için çalışan bilim insanlarına kumarin ve fonksiyonel grupları arasındaki yapı aktivite ilişkisi açısından fikir vereceği düşünülmektedir.

Keywords

SARS-CoV-2, COVID-19, Koronavirüs, Kumarin, İlaç tasarımı, Moleküler yerleştirme

References

• REFERENCES
• [1] Heidary, F., Gharebaghi, R. “Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen” The Journal of antibiotics, (2020),73(9), 593-602.
• [2] Lai, C-C., Shih, T-P., Ko, W-C., Tang, H-J., Hsueh, P-R. “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges” International journal of antimicrobial agents, (2020), 55(3), 105924.
• [3] Xu, P., Zhou, Q., Xu, J. “Mechanism of thrombocytopenia in COVID-19 patients” Annals of hematology, (2020), 99(6), 1205-1208.
• [4] Jain U. Effect of COVID-19 on the Organs. Cureus. 2020;12(8).
• [5] Khailany, R.A., Safdar, M., Ozaslan, M. “Genomic characterization of a novel SARS-CoV-2” Gene reports, (2020), 19, 100682.
• [6] Mittal, A., Manjunath, K., Ranjan, R.K., Kaushik, S., Kumar, S., Verma, V. “COVID-19 pandemic: Insights into structure, function, and hACE2 receptor recognition by SARS-CoV-2” PLoS pathogens, (2020), 16(8), e1008762.
• [7] Hall, Jr D.C., Ji, H-F. “A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease” Travel medicine and infectious disease, (2020), 35, 101646.
• [8] Dehelean, C.A., Lazureanu, V., Coricovac, D., Mioc, M,. Oancea, R., Marcovici, I., et al. “SARS-CoV-2: repurposed drugs and novel therapeutic approaches—insights into chemical structure—biological activity and toxicological screening” Journal of clinical medicine, (2020), 9(7), 2084.
• [9] Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., et al. “Structural and functional basis of SARS-CoV-2 entry by using human ACE2” Cell, (2020), 181(4), 894-904.
• [10] Hati, S., Bhattacharyya, S. “Impact of Thiol–Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor” ACS omega, (2020), 5(26), 16292-16298.
• [11] Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., et al. “The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice” Nature, (2020), 583(7818), 830-833.
• [12] Sun, X-Y., Liu, T., Sun, J., Wang, X-J. “Synthesis and application of coumarin fluorescence probes” RSC Advances, (2020), 10(18), 10826-10847.
• [13] Küpeli Akkol, E,. Genç, Y., Karpuz, B., Sobarzo-Sánchez, E., Capasso, R. “Coumarins and coumarin-related compounds in pharmacotherapy of cancer” Cancers, (2020), 12(7), 1959.
• [14] Pivetta, T., Valletta, E., Ferino, G., Isaia, F., Pani, A., Vascellari, S., et al. “Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity” Journal of inorganic biochemistry, (2017), 177, 101-109.
• [15] Basile, A., Sorbo, S., Spadaro, V., Bruno, M., Maggio, A., Faraone, N., et al. “Antimicrobial and antioxidant activities of coumarins from the roots of Ferulago campestris (Apiaceae)” Molecules, (2009), 14(3), 939-952.
• [16] Golfakhrabadi, F., Abdollahi, M., Ardakani, M.R.S., Saeidnia, S., Akbarzadeh, T., Ahmadabadi, A.N., et al. “Anticoagulant activity of isolated coumarins (suberosin and suberenol) and toxicity evaluation of Ferulago carduchorum in rats” Pharmaceutical biology, (2014), 52(10), 1335-1340.
• [17] Shen, Y-F., Liu, L., Feng, C-Z., Hu, Y., Chen, C., Wang, G-X., et al. “Synthesis and antiviral activity of a new coumarin derivative against spring viraemia of carp virüs” Fish & shellfish immunology, (2018), 81, 57-66.
• [18] Singh, L.R., Avula, S.R., Raj, S., Srivastava, A., Palnati, G.R., Tripathi, C., et al. “Coumarin–benzimidazole hybrids as a potent antimicrobial agent: synthesis and biological elevation” The Journal of antibiotics, (2017), 70(9), 954-961.
• [19] Hu, Y., Shen, Y., Wu, X., Tu, X., Wang, G-X. “Synthesis and biological evaluation of coumarin derivatives containing imidazole skeleton as potential antibacterial agents” European journal of medicinal chemistry, (2018), 143, 958-969.
• [20] Lingaraju, G.S., Balaji, K.S., Jayarama, S., Anil, S.M., Kiran, K.R., Sadashiva, M.P. “Synthesis of new coumarin tethered isoxazolines as potential anticancer agents” Bioorganic & medicinal chemistry letters, (2018), 28(23-24), 3606-3612.
• [21] Özdemir, M., Köksoy, B., Ceyhan, D., Bulut, M., YALCİN, B. “In silico, 6LU7 protein inhibition using dihydroxy-3-phenyl coumarin derivatives for SARS-CoV-2” Journal of the Turkish Chemical Society Section A: Chemistry. (2020) 7(3), 691-712.
• [22] Özdemir, M., Köksoy, B., Ceyhan, D., Sayın, K., Erçağ, E., Bulut, M., et al. “Design and in silico study of the novel coumarin derivatives against SARS-CoV-2 main enzymes” Journal of Biomolecular Structure and Dynamics, (2020), 1-16.
• [23] Kow, C.S., Sunter, W., Bain, A., Zaidi, S.T.R., Hasan, S.S. “Management of outpatient warfarin therapy amid COVID-19 pandemic: a practical guide” American Journal of Cardiovascular Drugs, (2020), 20, 301-309.
• [24] Trott, O., Olson, A.J. “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading” Journal of computational chemistry, (2010), 31(2), 455-461.
• [25] Yin, W., Mao, C., Luan, X., Shen, D-D., Shen, Q., Su, H., et al. “Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir” Science, (2020), 368(6498), 1499-1504.
• [26] BIOVIA DS. Discovery Studio Visualizer. San Diego: Dassault Systèmes2021.
• [27] Schrödinger. Maestro. Release 2021-2 ed. LLC, New York, NY: Schrödinger; 2021.
• [28] Daina, A., Michielin, O., Zoete, V. “SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules” Scientific reports, (2017), 7(1), 1-13.
• [29] Banerjee, P., Eckert, A.O., Schrey, A.K., Preissner, R. “ProTox-II: a webserver for the prediction of toxicity of chemicals” Nucleic acids research, (2018), 46(W1), W257-W63.
• [30] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings” Advanced drug delivery reviews, (1997), 23(1-3), 3-25.