Inhibition of pancreatic cancer via LPAR4 receptor with a de novo drug complex design using theoretical organic chemistry: Comprehensive molecular docking, molecular dynamics

Year 2024, Volume: 28 Issue: 4, 1033 - 1040, 28.06.2025

Soykan Agar , Yaren Arasan , Barbaros Akkurt , Engin Ulukaya

Abstract

The present work relates to a de novo organic chemistry involved drug design and repurposing discovery of a Quercetin and Ascorbic Acid complex formation with the IUPAC nomenclature of ‘’3-((2S)-2- (3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethoxy)-2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxychroman-4-one’’ to suppress pancreatic cancer via the inhibition of LPAR4 receptor. This was achieved with molecular docking and molecular dynamics studies and found that Ascorbic Acid is docking manoeuvre assistant for Quercetin to form Hydrogen bonds and Covalent bonds to shut down LPAR4 receptor with excellent inhibition constant. This study may very well lead to further in vitro organic synthesis, characterization and cell line results and in vivo/ex ovo animal testing for etherical bound Quercetin and Ascorbic Acid complex.

Keywords

Pancreatic Cancer , LPAR4 , Quercetin , Ascorbic Acid , Vitamin C , Molecular Docking , Molecular Dynamics , in silico drug design and repurposing.

References

• [1] National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Pancreatic Cancer. 2020 [cited 2023 Dec 28]. Cancer Stat Facts: Pancreatic Cancer. Available from: https://seer.cancer.gov/statfacts/html/pancreas.html
• [2] Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. The Lancet. 2016;388(10039):73–85. https://doi.org/10.1016/S0140-6736(16)00141-0.
• [3] Ravishankar D, Rajora AK, Greco F, Osborn HM. Flavonoids as prospective compounds for anti-cancer therapy. Int J Biochem Cell Biol. 2013 Dec;45(12):2821-31. https://doi.org/10.1016/j.biocel.2013.10.004.
• [4] Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, Büsselberg D. Flavonoids in cancer and apoptosis. Cancers (Basel). 2018;11(1):28. https://doi.org/10.3390/cancers11010028.
• [5] Liskova A, Koklesova L, Samec M, Smejkal K, Samuel SM, Varghese E, Abotaleb M, Biringer K, Kudela E, Danko J, Shakibaei M, Kwon TK, Büsselberg D, Kubatka P. Flavonoids in cancer metastasis. Cancers (Basel). 2020;12(6):1498. https://doi.org/10.3390/cancers12061498.
• [6] Murakami A, Ashida H, Terao J. Multitargeted cancer prevention by quercetin. Cancer Lett. 2008;269(2):315-325. https://doi.org/10.1016/j.canlet.2008.03.046.
• [7] Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E, Bertoncelli L, Cooper EL, Cossarizza A. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med. 2011;2011:591356. https://doi.org/10.1093/ecam/neq053.
• [8] Reyes-Farias M, Carrasco-Pozo C. The Anti-Cancer Effect of Quercetin: Molecular ımplications in cancer metabolism. Int J Mol Sci. 2019;20(13):3177. https://doi.org/10.3390/ijms20133177
• [9] Baghel SS, Shrivastava N, Baghel RS, Agrawal P, Rajput S. A review of quercetin: Antioxidant and anticancer properties. World J Pharm Pharmaceut Sci. 2012;1(1):146–160.
• [10] Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012;1826(2):443-57. https://doi.org/10.1016/j.bbcan.2012.06.003.
• [11] Ngo B, Van Riper JM, Cantley LC, Yun J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019;19(5):271-282. https://doi.org/10.1038/s41568-019-0135-7.
• [12] Bedhiafi T, Inchakalody VP, Fernandes Q, Mestiri S, Billa N, Uddin S, Merhi M, Dermime S. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother. 2022;146:112553. https://doi.org/10.1016/j.biopha.2021.112553.
• [13] Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer. 2003;3(8):582-591. https://doi.org/10.1038/nrc1143.
• [14] Llona-Minguez S, Ghassemian A, Helleday T. Lysophosphatidic acid receptor (LPAR) modulators: The current pharmacological toolbox. Prog Lipid Res. 2015;58:51-75. https://doi.org/10.1016/j.plipres.2015.01.004.
• [15] Umezu-Goto M, Tanyi J, Lahad J, Liu S, Yu S, Lapushin R, Hasegawa Y, Lu Y, Trost R, Bevers T, Jonasch E, Aldape K, Liu J, James RD, Ferguson CG, Xu Y, Prestwich GD, Mills GB. Lysophosphatidic acid production and action: validated targets in cancer? J Cell Biochem. 2004;92(6):1115-1140. https://doi.org/10.1002/jcb.20113.
• [16] Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P, Kennedy AW, Belinson J, Markman M, Casey G. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA. 1998;280(8):719-723. https://doi.org/10.1001/jama.280.8.719.
• [17] Kaffe E, Magkrioti C, Aidinis V. Deregulated lysophosphatidic acid metabolism and signaling in liver cancer. Cancers (Basel). 2019;11(11):1626. https://doi.org/10.3390/cancers11111626.
• [18] Lv GM, Li P, Wang WD, Wang ShK, Chen JF, Gong YL. Lysophosphatidic acid (LPA) and endothelial differentiation gene (Edg) receptors in human pancreatic cancer. J Surg Oncol. 2011;104(6):685–691. https://doi.org/10.1002/jso.22016.
• [19] Balijepalli P, Sitton CC, Meier KE. Lysophosphatidic acid signaling in cancer cells: What makes LPA so special? Cells. 2021;10(8):2059. https://doi.org/10.3390/cells10082059.
• [20] Wu C, Rakhshandehroo T, Wettersten HI, Campos A, von Schalscha T, Jain S, Yu Z, Tan J, Mose E, Childers BG, Lowy AM, Weis SM, Cheresh DA. Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation. Nat Cell Biol. 2023;25(2):309-322. https://doi.org/10.1038/s41556-022-01055-y.
• [21] Arnold F, Sherman MH. LPAR4 establishes a tumour-initiating niche. Nat Cell Biol. 2023;25(2):217-219. https://doi.org/10.1038/s41556-022-01038-z.
• [22] Li GS, Martins-Costa MTC, Millot C, Ruiz-López MF. AM1/TIP3P molecular dynamics simulation of imidazole proton-relay processes in aqueous solution. Chem Phys Lett. 1998;297(1–2):38–44. https://doi.org/10.1016/S0009-2614(98)01128-2.
• [23] Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09, Revision D.01. Wallingford, CT: Gaussian, Inc.; 2009. (Accessed 20 Jan, 2024)
• [24] Dennington R, Keith TA, Millam JM. GaussView Version 6. 2019. (Accessed 20 Jan, 2024)
• [25] Avogadro Chemistry. Avogadro [Internet]. 2016. Available from: http://avogadro.cc/ (Accessed 20 Jan, 2024)
• [26] DeLano WL. Pymol: An open-source molecular graphics tool. CCP4 Newsl Protein Crystallogr. 2002;40(1):82–92.
• [27] Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 2021;61(8):3891–3898. https://doi.org/10.1021/acs.jcim.1c00203.
• [28] Desmond D. Desmond. New York: Shaw Research; 2017. (Accessed 20 Jan, 2024)
• [29] Evans DJ, Holian BL. The Nose–Hoover thermostat. J Chem Phys. 1985;83(8):4069–4074. https://doi.org/10.1063/1.449071.
• [30] Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys. 1994;101(5):4177–4189. https://doi.org/10.1063/1.467468.