In Silico Screening of the Phenolic Compound Oleuropein and Its Hydrolysis Product 3-Hydroxytyrosol Against Certain Structural and Non-Structural Proteins of SARS-CoV- 2

Yıl 2021, Cilt: 8 Sayı: 3, 824 - 833, 26.07.2021

Erman Salih İstifli

https://doi.org/10.30910/turkjans.953603

Öz

The novel corona virus has infected nearly 163 million people globally as of May 2021 and caused death of more than 3.3 million patients. Despite intense efforts, however, a small molecule with full therapeutic potential has not been developed in the treatment of SARS-CoV-2. The aim of this study was to investigate the inhibitory potentials of oleuropein and its hydrolysis product 3-hydroxytyrosol against spike glycoprotein, papain-like protease, main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular modelling simulations. Compared to 3-hydroxytyrosol, oleuropein showed stronger binding affinity to all targets in docking, and its affinity to Mpro (-7.0 kcal mol-1) and RdRp (-8.0 kcal mol-1) was quite high. Despite the Mpro-oleuropein complex, the RdRp-oleuropein complex showed a highly stable binding in 15-ns molecular dynamics based on root-mean-square-deviation (0.14 - 0.32 nm) and hydrogen bond numbers (6.85). The intracellular targets of oleuropein covered various proteases (17%), enzymes (16%), family A G protein-coupled receptors (11%), kinases (10%) and other cytosolic proteins (10%), however, probabilistic analysis showed that oleuropein was unlikely (p = 0 - 0.22) to bind these targets. ADMET profile showed that, with few exceptions, oleuropein has the physicochemistry that should be present in a drug molecule. In conclusion, oleuropein binds tightly to the active site of RdRp and could inhibit this enzyme. Oleuropein may be used alone or in combination with replicase inhibitors such as remdesivir or favipiravir in the treatment of COVID-19. Additional in vitro binding assays and in vivo efficacy studies are needed to prove our findings.

Anahtar Kelimeler

Oleuropein, 3-hydroxytyrosol, SARS-CoV-2, Molecular docking, Molecular dynamics

Fenolik Bileşik Oleuropein ve Hidroliz Ürünü 3-Hidroksitirozol'ün SARS-CoV-2'nin Bazı Yapısal ve Yapısal Olmayan Proteinlerine Karşı In Siliko Etkinliği

Öz

Yeni tip korona virüsü Mayıs 2021 itibariyle dünya genelinde yaklaşık 163 milyon kişiyi enfekte etmiş ve 3.3 milyondan fazla hastanın ölümüne neden olmuştur. Yoğun çalışmalara rağmen SARS-CoV-2 tedavisinde tam koruma sağlayan terapötik potansiyelli bir ilaç geliştirilememiştir. Bu çalışmanın amacı, moleküler modelleme simülasyonları kullanarak oleuropein ve onun hidroliz ürünü 3-hidroksitirosol’ün SARS-CoV-2 spike glikoproteini, papain-benzeri proteazı (PLpro), ana proteazı (Mpro) ve RNA-bağımlı RNA polimerazına (RdRp) karşı inhibitör potansiyellerini araştırmaktır. 3-hidroksitirosol ile karşılaştırıldığında oleuropein, moleküler doking analizinde tüm protein hedeflere daha yüksek bağlanma afinitesi göstermekle beraber Mpro (-7.0 kcal/mol) ve RdRp'ye (-8.0 kcal/mol) karşı afinitesi oldukça yüksek bulunmuştur. Kök-ortalama-kare-sapması (0.14 - 0.32 nm) ve hidrojen bağı sayısı (6.85) göz önüne alındığında, Mpro-oleuropein kompleksinin aksine, RdRp-oleuropein kompleksi 15 nanosaniyelik moleküler dinamik analizinde oldukça kararlı bir bağlanma sergilemiştir. Oleuropein’in intraselüler hedefleri arasında çeşitli proteazlar (%17), enzimler (%16), G protein-bağlı reseptörler (%11), kinazlar (%10) ve diğer sitozolik proteinler (%10) bulunmasına rağmen, olasılık analizlerine göre oleuropein’in bu hedeflere bağlanma olasılığı oldukça düşük bulunmuştur (p = 0 - 0.22). Birkaç istisna dışında oleuropein'in absorbsiyon-dağılım-metabolizma-atılım-toksisite (ADMET) profili, bir ilaç molekülünde bulunması gereken fizikokimyasal özelliklere sahip olduğunu göstermiştir. Sonuç olarak oleuropein, RdRp'nin aktif bölgesine sıkıca bağlanma ve bu enzimi inhibe etme potansiyeline sahiptir. Oleuropein, COVID-19 tedavisinde tek başına ya da remdesivir veya favipiravir gibi replikaz inhibitörleri ile birlikte kullanılabilir. Bulgularımızın kanıtlanması için ilave in vitro ilaç-bağlanma ve in vivo etkinlik çalışmalarına ihtiyaç duyulmaktadır.

Anahtar Kelimeler

Oleuropein, 3-hidroksitirosol, SARS-CoV-2, RdRp, Moleküler doking, Moleküler dinamik

Kaynakça

• Abd El-Aziz, N.M., Shehata, M.G., Awad, O.M.E., El-Sohaimy, S.A. 2020. Inhibition of COVID-19 RNA-Dependent RNA Polymerase by Natural Bioactive Compounds: Molecular Docking Analysis. Preprints (In press). DOI: https://doi.org/10.21203/rs.3.rs-25850/v1.
• Abraham, M.J., Murtola, T., Schulz, R., Páll, S., Smith, J.C., Hess, B., Lindahl, E. 2015. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1–2, 19-25.
• Altay, O., Mohammadi, E., Lam, S., Turkez, H., Boren, J., Nielsen, J., Uhlen, M., Mardinoglu, A. 2020. Current Status of COVID-19 Therapies and Drug Repositioning Applications. iScience, 23, 101303.
• Berendsen, H.J., Postma, J.P., van Gunsteren, W.F., Hermans, J. 1981. Interaction models for water in relation to protein hydration, in: B., P. (Ed.), Intermolecular forces, 331-342.
• Chojnacka, K., Witek-Krowiak, A., Skrzypczak, D., Mikula, K., Młynarz, P. 2020. Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus. J. Funct. Foods, 73, 104146.
• Daina, A., Michielin, O., Zoete, V. 2019. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res, 47, 357-364.
• Denison, M.R., Graham, R.L., Donaldson, E.F., Eckerle, L.D., Baric, R.S. 2011. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol, 8, 270-279.
• Fehr, A.R., Perlman, S. 2015. Coronaviruses: an overview of their replication and pathogenesis. Coronaviruses, 1282, 1-23.
• Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.-H., Nitsche, A. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181, 271-280.
• Jackson, L.A., Anderson, E.J., Rouphael, N.G., Roberts, P.C., Makhene, M., Coler, R.N., McCullough, M.P., Chappell, J.D., Denison, M.R., Stevens, L.J. 2020. An mRNA vaccine against SARS-CoV-2—preliminary report. New Engl. J. Med., 383, 1920-1931.
• Kandeel, M., Kitade, Y., Almubarak, A. 2020. Repurposing FDA-approved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase. PeerJ, 8, e10480.
• Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., Soetjipto, S. 2020. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints, 2020030226 (doi: 10.20944/preprints202003.0226.v1).
• Lee-Huang, S., Huang, P.L., Zhang, D., Lee, J.W., Bao, J., Sun, Y., Chang, Y.T., Zhang, J., Huang, P.L. 2007. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. fusion [corrected] inhibition. Biochem. Biophys. Res. Commun., 354, 872-878.
• Li, H., Robertson, A.D., Jensen, J.H. 2005. Very fast empirical prediction and rationalization of protein pKa values. Proteins, 61, 704-721.
• Ma, S.C., He, Z.D., Deng, X.L., But, P.P., Ooi, V.E., Xu, H.X., Lee, S.H., Lee, S.F. 2001. In vitro evaluation of secoiridoid glucosides from the fruits of Ligustrum lucidum as antiviral agents. Chem. Pharm. Bull., 49, 1471-1473.
• Malde, A.K., Zuo, L., Breeze, M., Stroet, M., Poger, D., Nair, P.C., Oostenbrink, C., Mark, A.E. 2011. An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0. J. Chem. Theory Comput., 7, 4026-4037.
• Monteil, V., Kwon, H., Prado, P., Hagelkrüys, A., Wimmer, R.A., Stahl, M., Leopoldi, A., Garreta, E., Del Pozo, C.H., Prosper, F. 2020. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell, 181, 905-913. e907.
• Omar, S.H. 2010. Oleuropein in olive and its pharmacological effects. Sci. Pharm., 78, 133-154.
• 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 computer-aided molecular design, 18, 167-173.
• Pires, D.E., Blundell, T.L., Ascher, D.B. 2015. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem., 58, 4066-4072.
• Raoult, D., Zumla, A., Locatelli, F., Ippolito, G., Kroemer, G. 2020. Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses. Cell Stress, 4, 66.
• Sarikurkcu, C., Ozer, M.S., Istifli, E.S., Sahinler, S.S., Tepe, B. 2021. Chromatographic profile and antioxidant and enzyme inhibitory activity of Sideritis leptoclada: An endemic plant from Turkey. South African Journal of Botany, Doi: https://doi.org/10.1016/j.sajb.2021.03.020.
• Trott, O., Olson, A.J. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 31, 455-461.
• Valdes-Tresanco, M.S., Valdes-Tresanco, M.E., Valiente, P.A., Moreno, E. 2020. AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biol. Direct, 15, 12.
• Vicenti, I., Zazzi, M., Saladini, F. 2021. SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19. Expert Opin. Ther. Pat., 31, 325-337.
• Vijayan, R., Gourinath, S. 2021. Structure-based inhibitor screening of natural products against NSP15 of SARS-CoV-2 revealed thymopentin and oleuropein as potent inhibitors. J. Proteins Proteom., https://doi.org/10.1007/s42485-021-00059-w.
• Wang, Y., Liu, M., Gao, J. 2020. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc. Natl. Acad. Sci. USA, 117, 13967-13974.