In Silico Evaluation of ERQ Bioactive Tripeptide as an Anticancer Agent and an Inhibitor of SARS-CoV-2 Enzymes

Year 2024, , 34 - 41, 30.05.2024

Gözde Yılmaz , Sefa Çelik , Ayşen Erbölükbaş Özel , Sevim Akyüz

https://doi.org/10.26650/EurJBiol.2024.1389569

Abstract

Objective: Short peptides play a significant role in exploring drugs with higher selectivity and fewer side effects in cancer and COVID-19 therapies. This study evaluated the anticancer and anti-COVID-19 activities of Glu-Arg-Gln (ERQ) tripeptide for the first time. To discover the potentiality of the tripeptide as an anticancer and as a SARS-CoV-2 inhibitor, molecular docking analysis of ERQ tripeptide with DNA (PDB ID: 1BNA) and a variety of SARS-CoV-2 enzymes, namely. Main protease (PDB IDs: 6M03, 6LU7) and Spike glycoprotein (PDB ID: 6VXX) were performed.
Materials and Methods: To determine the binding efficiency of ERQ to target DNA and proteins, molecular docking processes were carried out using the Autodock Vina program. The sorts of bonds and interacting residues in ERQ/DNA and ERQ/protein complexes were determined.
Results: Molecular docking simulations of ERQ tripeptide against 1BNA, 6M03, 6LU7, and 6VXX were performed, and the interactions between the docked ligand and target residues were determined. The binding mechanisms of ERQ with the receptors were clarified. The binding affinities of ERQ towards the targets were predicted to be between -6.3 and -6.7 kcal/mol. ERQ showed the highest binding affinity to Spike glycoprotein (6VXX), with an estimated binding energy of -6.7 kcal/mol.
Conclusion: Molecular docking simulations revealed the potential of ERQ tripeptide as an anticancer and anti-COVID-19 agent. High binding affinity against 1BNA (-6.4 kcal/mol), 6M03 (-6.3 kcal/mol), 6LU7 (-6.6 kcal/mol), and 6VXX (-6.7 kcal/mol) indicated that ERQ could be an excellent new natural therapy for the treatment of cancer and COVID-19.

Keywords

In silico, Molecular docking, Glu-Arg-Gln, ERQ, Tripeptide

Supporting Institution

Research funds of Istanbul University

Project Number

FDK-2023-39504

Thanks

This study was supported by the Research funds of Istanbul University (FDK-2023-39504).

References

• Nikfar Z, Shariatinia Z. The RGD tripeptide anticancer drug car-rier: DFT computations and molecular dynamics simulations. J Mol Liq. 2019;281:565-583. google scholar
• Sun A, Shoji M, Lu YJ, Liotta DC, Snyder, JP. Synthesis of EF24-tripeptide chloromethyl ketone: A novel curcumin-related anticancer drug delivery system. J Med Chem. 2006;49(11):3153-3158. google scholar
• Ali H, Jabeen A, Maharjan, R, et al. Furan-conjugated tripep-tides as potent antitumor drugs. Biomolecules. 2020;10(12):1684. doi:10.3390/biom10121684 google scholar
• Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26(10):2700-2707. google scholar
• Ye N, Ding Y, Wild C, Shen Q, Zhou J. Small molecule inhibitors targeting activator protein 1 (AP-1). J Med Chem. 2014;57(16):6930-6948. google scholar
• Kumar A, Kothari J, Lokhande KB, Seethamma TN, Venkateswara Swamy K, Sharma NK. Novel antiproliferative tripeptides inhibit AP-1 transcriptional complex. Int J Pept Res Ther. 2021;27(4):2163-2182. google scholar
• Fan J, Fu A, Zhang L. Progress in molecular docking. Quant Biol. 2019;7(2):83-89. google scholar
• Pagadala NS, Syed K, Tuszynski J. Software for molecular dock-ing: A review. Biophys Rev. 2017;9(2):91-102. google scholar
• Gilad Y, Senderowitz H. Docking studies on DNA intercalators. J Chem Inf Model. 2014;54(1):96-107. google scholar
• Celik S, Vagifli F, Akyuz S, et al. Synthesis, vibrational spec-troscopic investigation, molecular docking, antibacterial and an-timicrobial studies of a new anthraquinone derivative compound. Spectrosc Lett. 2022;55(4):259-277. google scholar
• Protein Data Bank website. http://www.rcsb.org/pdb. Accessed November 09, 2023. google scholar
• Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem. 1996;17(5-6):490-519. google scholar
• Shao Y, Molnar LF, Jung Y, et al. Advances in methods and algorithms in a modern quantum chemistry program package. Phys Chem Chem Phys. 2006;8(27):3172-3191. google scholar
• Trott O, Olson AJ. Autodock vina: Improving the speed and accu-racy of docking with a new scoring function, efficient optimiza-tion, and multithreading. J Comput Chem. 2010;31:455-461. google scholar
• Drew HR, Wing RM, Takano T, et al. Structure of a B-DNA do-decamer: Conformation and dynamics. Proc Natl Acad Sci USA. 1981;78(4): 2179-2183. google scholar
• Zhao Y, Zhu Y, Liu X, et al. Structural basis for repli-case polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2. Proc Natl Acad Sci USA. 2022;119(16):e2117142119. doi:10.1073/pnas.2117142119 google scholar
• Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289-293. google scholar
• Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181(2):281-292. google scholar
• Jurcik A, Bednar D, Byska J, et al. Caver analyst 2.0: Anal-ysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectories. Bioinformatics. 2018;34(20):3586-3588. google scholar
• Demirag AD, Çelik S, Akyuz S, Ozel A. Molecular docking anal-ysis of used drugs for the treatment of cancer. Süleyman Demirel University J Nat App Sci. 2021;25(3):539-547. google scholar
• Sagaama A, Brandan SA, Issa TB, Issaoui N. Searching po-tential antiviral candidates for the treatment of the 2019 novel coronavirus based on DFT calculations and molecular docking. Heliyon. 2020;6(8): e04640. doi:10.1016/j.heliyon.2020.e04640 google scholar
• Arifa Begum SK, Begum S, Bandari P, Swapna BS, Reddemma M. Tetrandrine, an effective inhibitor of COVID-19 main protease (Mpro); Insights from molecular docking and dynamics simula-tions. Int J Pharm Investig. 2023;13(4):845-851. google scholar
• Celik S, Yilmaz G, Akyuz S, Ozel AE. Shedding light into the bio-logical activity of aminopterin, via molecular structural, docking, and molecular dynamics analyses. J Biomol Struct Dyn. 2023;1-22. doi:10.1080/07391102.2023.2245493 google scholar
• Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coron-avirus M protease from clinically approved medicines. J Genet Genomics. 2020;47(2):119-121. google scholar
• Özdemir M, Köksoy B, Ceyhan D, Bulut M, Yalcin B. In silico, 6LU7 protein inhibition using dihydroxy-3-phenyl coumarin derivatives for SARS-CoV-2. J Turk Chem Soc Sect A Chem. 2020;7(3):691-712. google scholar
• Hatada R, Okuwaki K, Mochizuki Y, et al. Fragment molecular orbital based interaction analyses on COVID-19 main protease-inhibitor n3 complex (PDB ID:6LU7). J Chem Inf Model. 2020;60(7):3593-3602. google scholar
• Celik S, Akyuz S, Ozel AE. Vibrational spectroscopic characterization and structural investigations of cepharan-thine, a natural alkaloid. J Mol Struct. 2022;1258:132693. https://doi.org/10.1016/j.molstruc.2022.132693 google scholar
• Holanda VN, Lima EMDA, Silva WVD, et al. Identification of 1, 2, 3-triazole-phthalimide derivatives as potential drugs against COVID-19: A virtual screening, docking and molecular dynamic study. J Biomol Struct Dyn. 2022;40(12):5462-5480. google scholar
• Joshi A, Sharma V, Singh J, Kaushik V. Chemi-informatic ap-proach to investigate putative pharmacoactive agents of plant ori-gin to eradicate COVID-19. Coronaviruses. 2022;3(3):40-54. google scholar