Comprehensive In Silico Characterization of Phenolic Compounds: Structural Optimization, Molecular Docking, and ADMET Profiling of Potential Syncytin-2 Inhibitors for Glioblastoma and Lung Cancer Therapeutics

Year 2025, Volume: 11 Issue: 1, 18 - 29, 21.03.2025

Aliye Demet Demirağ , Hatice Güngör

https://doi.org/10.30934/kusbed.1610257

Abstract

Objective: To investigate the interactions between selected phenolic compounds (hesperidin, naringin, neohesperidin, kaempferol, apigenin, hesperetin, and nobiletin) and syncytin-2 protein, evaluating their potential as novel therapeutic agents for glioblastoma and lung cancer treatment.

Methods: Molecular docking simulations were employed to analyze phenolic compound-syncytin-2 protein interactions. Comprehensive in silico ADMET analyses were conducted to assess pharmacokinetic properties and toxicity profiles of the compounds.

Results: Hesperidin and neohesperidin exhibited the highest affinity to syncytin-2, with binding affinities of -10.5 kcal/mol and -10.0 kcal/mol, respectively. Molecular-level analyses demonstrated that hesperidin forms critical hydrogen bonds and hydrophobic interactions with Isoleucine 371, Alanine 372, and Leucine 309 amino acid residues. ADMET analyses revealed that these two compounds exhibit low toxicity potential and optimal pharmacokinetic profiles.

Conclusion: This research provides evidence that phenolic compounds may serve as inhibitors of syncytin-2 in the treatment of glioblastoma and lung cancer. The identified molecular interactions and promising ADMET profiles support the need for further investigation of these compounds. Future studies should focus on optimizing phenolic compound-based inhibitors, conducting preclinical and clinical evaluations, and assessing their potential therapeutic effects within the tumor microenvironment.

Keywords

Glioblastoma multiforme, lung cancer, syncytin-2, phenolic compounds, molecular docking, ADMET analysis

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660.
• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492.
• Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299-312. doi:10.3322/caac.21613.
• Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-454. doi:10.1038/nature25183.
• Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330.
• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708.
• Pucci C, Martinelli C, Ciofani G. Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience. 2019;13:961. doi:10.3332/ecancer.2019.961.
• Soygur B, Sati L. The role of syncytins in human reproduction and reproductive organ cancers. Reproduction. 2016;152(5):R167-R178. doi:10.1530/REP-16-0031.
• Kudaka W, Oda T, Jinno Y, Yoshimi N, Aoki Y. Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension. Placenta. 2008;29(3):282-289. doi:10.1016/j.placenta.2007.12.006.
• Mi S, Lee X, Li XP, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature. 2000;403(6771):785-789. doi:10.1038/35001608.
• Larsen JM, Christensen IJ, Nielsen HJ, et al. Syncytin immunoreactivity in colorectal cancer: potential prognostic impact. Cancer Lett. 2009;280(1):44-49. doi:10.1016/j.canlet.2009.02.008.
• Liang CY, Wang LJ, Chen CP, et al. GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biol Reprod. 2010;83(3):387-395. doi:10.1095/biolreprod.110.083915.
• Maliniemi P, Vincendeau M, Mayer J, et al. Expression of human endogenous retrovirus-w including syncytin-1 in cutaneous T-cell lymphoma. PLoS One. 2013;8(10):e76281. doi:10.1371/journal.pone.0076281.
• Bastida-Ruiz D, Van Hoesen K, Cohen M. The dark side of cell fusion. Int J Mol Sci. 2016;17(5):638. doi:10.3390/ijms17050638.
• Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res. 2009;69(22):8536-8539. doi:10.1158/0008-5472.CAN-09-2159.
• Michaud J, Simpson KM, Escher R, et al. Integrative analysis of RUNX1 downstream pathways and target genes. BMC Genomics. 2008;9:363. doi:10.1186/1471-2164-9-363.
• Bolze PA, Patrier S, Cheynet V, et al. Expression patterns of ERVWE1/Syncytin-1 and other placentally expressed human endogenous retroviruses along the malignant transformation process of hydatidiform moles. Placenta. 2016;39:116-124. doi:10.1016/j.placenta.2016.01.011.
• Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009;2(5):270-278. doi:10.4161/oxim.2.5.9498.
• Cory H, Passarelli S, Szeto J, Tamez M, Mattei J. The role of polyphenols in human health and food systems: A mini-review. Front Nutr. 2018;5:87. doi:10.3389/fnut.2018.00087.
• Zhou Y, Zheng J, Li Y, et al. Natural polyphenols for prevention and treatment of cancer. Nutrients. 2016;8(8):515. doi:10.3390/nu8080515.
• Hussain T, Tan B, Yin Y, et al. Oxidative stress and inflammation: what polyphenols can do for us?. Oxid Med Cell Longev. 2016;2016:7432797. doi:10.1155/2016/7432797
• Rauf A, Imran M, Khan IA, et al. Anticancer potential of quercetin: A comprehensive review. Phytother Res. 2018;32(11):2109-2130. doi:10.1002/ptr.6155.
• Rodríguez-García C, Sánchez-Quesada C, Toledo E, Delgado-Rodríguez M, Gaforio JJ. Naturally lignan-rich foods: A dietary tool for health promotion?. Molecules. 2019;24(5):917. doi:10.3390/molecules24050917.
• Dou H, Shen R, Tao J, et al. Curcumin suppresses the colon cancer proliferation by inhibiting Wnt/β-catenin pathways via miR-130a. Front Pharmacol. 2017;8:877. doi:10.3389/fphar.2017.00877.
• Luo H, Jiang BH, King SM, Chen YC. Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids. Nutr Cancer. 2008;60(6):800-809. doi:10.1080/01635580802100851.
• Chen AY, Chen YC. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013;138(4):2099-2107. doi:10.1016/j.foodchem.2012.11.139.
• Baek SH, Lee JH, Kim C, et al. Ginkgolic acid C 17:1, derived from Ginkgo biloba leaves, suppresses constitutive and inducible STAT3 activation through induction of PTEN and SHP-1 tyrosine phosphatase. Molecules. 2017;22(2):276. doi:10.3390/molecules22020276.
• Lee YC, Cheng TH, Lee JS, et al. Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol Cell Biochem. 2011;347:103-115. doi:10.1007/s11010-010-0621-4.
• Maia EHB, Assis LC, De Oliveira TA, Da Silva AM, Taranto AG. Structure-based virtual screening: from classical to artificial intelligence. Front Chem. 2020;8:343. doi:10.3389/fchem.2020.00343.
• World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.
• Kim S, et al. PubChem 2021 update. Nucleic Acids Research. 2021;49(D1):D1388-D1395. doi:10.1093/nar/gkaa971
• Jumper J, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583-589. doi:10.1038/s41586-021-03819-2.
• Frisch MJ, et al. Gaussian 09, Revision D.01. Journal of Computational Chemistry. 2009;30:2785-2791. doi:10.1002/jcc.21256.
• Morris GM, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry. 2009;30(16):2785-2791. doi:10.1002/jcc.21256.
• Trott O, Olson AJ. 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. doi:10.1002/jcc.21334.
• DeLano WL. PyMOL: An open-source molecular graphics tool. CCP4 Newsletter on Protein Crystallography. 2002;40:82-92. doi:10.1107/S0021889892009944.
• Dassault Systèmes BIOVIA. Discovery Studio Visualizer, Version 2021. San Diego, CA, USA. 2020. doi:10.1016/j.softx.2020.100589.
• Schrödinger Release 2021-1: Maestro. Schrödinger, LLC, New York, NY. 2021. doi:10.1002/jcc.26544.
• Sander T, et al. Data-driven prediction of drug-likeness using Osiris Property Explorer. Journal of Cheminformatics. 2015;7(1):1-11. doi:10.1186/s13321-015-0098-y.
• Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies. 2004;1(4):337-341. doi:10.1016/j.ddtec.2004.11.007.