MOLECULAR DOCKING STUDY AS THERAPEUTIC APPROACH FOR TARGETING CHOLECYSTOKININ IN PANCREATIC CANCER

OKTAVIAN ARYA PUTRA; TESIA AISYAH RAHMANIA; EDITHA RENESTEEN

doi:10.22159/ijap.2024v16i5.51027

Authors

OKTAVIAN ARYA PUTRA Faculty of Military Pharmacy, Republic of Indonesia Defense University, Bogor-16810, Indonesia
TESIA AISYAH RAHMANIA Faculty of Military Pharmacy, Republic of Indonesia Defense University, Bogor-16810, Indonesia https://orcid.org/0000-0002-7134-9547
EDITHA RENESTEEN Faculty of Military Pharmacy, Republic of Indonesia Defense University, Bogor-16810, Indonesia

DOI:

https://doi.org/10.22159/ijap.2024v16i5.51027

Keywords:

Pancreatic cancer, CCK, Molecular docking, In silico, 7F8U, Barberine

Abstract

Objective: The Cholecystokinin A receptor (CCK-ARs), also known as CCK1 receptor, is a type of G protein-coupled receptor that is primarily responsive to the hormone Cholecystokinin (CCK). CCK-ARs is one of the receptors characterized and validated to promote pancreatic cancer progression. Devazepide is a selective antagonist of the CCK-ARs. This study aims to find a potential ligand that has the most effective and representative interaction with cancer receptors, becoming a new therapeutic effect using molecular docking Molecular Operating Environment (MOE) with receptor code 7F8U.

Methods: We conducted an in silico study by docking candidate ligands with Cholecystokinin Receptor (CCKRs) using the MOE 2015 V.10 application. The ligands of choice come from natural ingredients such as curcumin, resveratrol, berberine, baicalein, dioscin, wogonin, and piperine. Validate the receptor with the Root mean Square Deviation (RMSD) value and docking results with the GIBBS S value.

Results: 6 compounds, such as curcumin, resveratrol, berberine, baicalein, wogonin, and piperine, were selected for docking as candidates to determine whether they have interactions with CCK-ARs. Based on the docking results, the Gibbs values obtained were -14.9522;-12.4566;-15.5033;-12.6961;-13.4234;-11,6130 joules/kg. mol, berberine is the compound with the lowest Gibbs energy, namely -15.5033 joules/kg. mol and is one of the strongest. The interactions that occur include Methionine A121-side chain donor, Methionine B121-side chain donor, asparagine A333-amine group and nitrogen atom, B333-amine group and nitrogen atom, Arginine A336-negative oxygen atom, and B336-negative oxygen atom.

Conclusion: Berberine which is a natural alkaloid, is suitable for devazepide, which is a positive control for ligand interactions when tethered to the CCKRs. This finding could be a potential new drug for pancreatic cancer. However, further studies, such as in vitro, in vivo, and clinical trials need to be conducted for ordering activity, safety, and safety of new drugs.

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References

Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011 Aug;378(9791):607-20. doi: 10.1016/S0140-6736(10)62307-0, PMID 21620466, PMCID PMC3062508.

Sadr Azodi O, Oskarsson V, Discacciati A, Videhult P, Askling J, Ekbom A. Pancreatic cancer following acute pancreatitis: a population-based matched cohort study. Am J Gastroenterol. 2018 Nov;113(11):1711-9. doi: 10.1038/s41395-018-0255-9, PMID 30315287.

Tuveson D. The early detection of pancreatic cancer in the U.S. military. MD; 2015 Oct.

Kim A, Ha J, Kim J, Cho Y, Ahn J, Cheon C. Natural products for pancreatic cancer treatment: from traditional medicine to modern drug discovery. Nutrients. 2021 Oct 26;13(11):34836055. doi: 10.3390/nu13113801, PMID 34836055, PMCID PMC8625071.

Smith JP, Wang S, Nadella S, Jablonski SA, Weiner LM. Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice. Cancer Immunol Immunother. 2018 Feb 17;67(2):195-207. doi: 10.1007/s00262-017-2077-9, PMID 29043413, PMCID PMC5801048.

Brown NJ, Rumsey RD, Read NW. The effect of the cholecystokinin antagonist devazepide (L364718) on the ileal brake mechanism in the rat. J Pharm Pharmacol. 1993;45(12):1033-6. doi: 10.1111/j.2042-7158.1993.tb07175.x, PMID 7908970.

Lattmann E, Sattayasai J, Narayanan R, Ngoc N, Burrell D, Balaram PN. Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease. Med Chem Comm. 2017;8(3):680-5. doi: 10.1039/c6md00707d, PMID 30108786, PMCID PMC6072330.

Offel M, Lattmann P, Singh H, Billington DC, Bunprakob Y, Sattayasai J. Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands. Arch Pharm (Weinheim). 2006 Apr 6;339(4):163-73. doi: 10.1002/ardp.200500217, PMID 16572480.

Pinzi L, Rastelli G. Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci. 2019 Sep 4;20(18):31487867. doi: 10.3390/ijms20184331, PMID 31487867, PMCID PMC6769923.

Baihaki MF, Wardhani BW, Renesteen E, Rahmania TA. Candidates targeted therapy of epidermal growth factor receptor for lung cancer: in silico study. J Southwest Jiaotong Univ. 2021 Dec 24;56(6):948-58. doi: 10.35741/issn.0258-2724.56.6.83.

Harahap A, Rahmania T, Renesteen E, Wardani B. In silico study: molecular docking targeting KRAS ReceptorIn Lung Cancer. Az Med J. 2022 Nov;62(09).

Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J Chem Inf Model. 2009 Feb 23;49(2):444-60. doi: 10.1021/ci800293n, PMID 19434845, PMCID PMC2788795.

Ruswanto R, Mardhiah M, Mardianingrum R, Novitriani K. Synthesis and in silico study of the compound 3-nitro-N′-[(pyridine-4-yl) carbonyl]benzohydrazide as an antituberculosis candidate. Chim Nat Acta. 2015 Aug 12;3(2):n2.9183.14. doi: 10.24198/cna.v3.n2.9183.

Smith JP, Fonkoua LK, Moody TW. The role of gastrin and CCK receptors in pancreatic cancer and other malignancies. Int J Biol Sci. 2016;12(3):283-91. doi: 10.7150/ijbs.14952, PMID 26929735, PMCID PMC4753157.

Fino KK, Matters GL, McGovern CO, Gilius EL, Smith JP. Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1244-52. doi: 10.1152/ajpgi.00460.2011, PMID 22442157, PMCID PMC3378167.

Mehdi S, Chauhan A, Dhutty A. Cancer and new prospectiveto treat cancer. Int J Curr Pharm Sci. 2023 Nov 15:16-22. doi: 10.22159/ijcpr.2023v15i6.3078.

Xu RX, Sun XC, Ma CY, Yao YH, Li XL, Guo YL. Original article impacts of berberine on oxidized LDL-induced proliferation of human umbilical vein endothelial cells. Am J Transl Res. 2017;9(10):4375-89. PMID 29118901, PMCID PMC5666048.

Zhang H, Bao X, Zhang J, Hu Q, Wei B. Devazepide suppresses cell proliferation and migration, and induces apoptosis in bladder carcinoma. Transl Androl Urol. 2021 May;10(5):2113-21. doi: 10.21037/tau-21-409, PMID 34159092, PMCID PMC8185656.

Baldwin GS, Shulkes A. CCK receptors and cancer. Curr Top Med Chem. 2007 Jun 1;7(12):1232-8. doi: 10.2174/156802607780960492, PMID 17584144.

Smith JP, Kramer S, Bagheri S. Effects of a high-fat diet and L364,718 on growth of human pancreas cancer. Dig Dis Sci. 1990 Jun;35(6):726-32. doi: 10.1007/BF01540175, PMID 2344806.

Zhang X, He C, Wang M, Zhou Q, Yang D, Zhu Y. Structures of the human cholecystokinin receptors bound to agonists and antagonists. Nat Chem Biol. 2021 Dec 23;17(12):1230-7. doi: 10.1038/s41589-021-00866-8, PMID 34556863.

Jain AN, Nicholls A. Recommendations for evaluation of computational methods. J Comput Aided Mol Des. 2008 Mar 13;22(3-4):133-9. doi: 10.1007/s10822-008-9196-5, PMID 18338228, PMCID PMC2311385.

DwiAgistia D, Purnomo H, Tegar M, Endro Nugroho A. Interaction between active compounds from Aegle marmelos correa as anti inflammation agent with COX-1 and COX-2 receptor. Interaction between active compounds from Aegle marmelos correa as anti-inflammation with COX-1 and COX-2 receptors. Traditional Medicine Journal. 2013;18(2):80-7.

Laksmiani NP, Vidya PNLP, Wirasuta MA. In vitro and in silico antioxidant activity of purified fractions from purple sweet potato ethanolic extract original article. Int J Pharm Pharm Sci. 2016;8(8):177-81.

Kurian T. In silico screeningby molecular docking of heterocyclic compounds with furan or indole nucleus from database for anticancer activity and validation of the method by redocking. Int J Pharm Pharm Sci. 2024 Apr 1:42-5. doi: 10.22159/ijpps.2024v16i4.50478.

Guo LD, Chen XJ, Hu YH, Yu ZJ, Wang D, Liu JZ. Curcumin inhibits proliferation and induces apoptosis of human colorectal cancer cells by activating the mitochondria apoptotic pathway. Phytother Res. 2013 Mar 25;27(3):422-30. doi: 10.1002/ptr.4731, PMID 22628241.

Effendi. Polarity theory and intermolecular forces. 2nd ed. Malang: Bayumedia Publishing; 2006. p. 1-290.

Prananta. Hydrogen bonding. Malang: Brawijaya University. Brawijaya University; 2013.

Kurniawan Y, Nur M. Modeling study of proton dynamics in hydrogen bonds H2O one-dimensional solids. Phys Period. 2005 Jul;8(3):107-17.

Bare Y. Analysis of phytosterol compounds of cymbopogon citratus and curcuma longa as antialzheimer's. Biopendix: Jurnal Biologi, Pendidikan & Terapan. 2021;7:153-9. doi: 10.30598/biopendixvol7issue2page153-159.

Elfi TN, Bunga YN, Bare Y. In silico biological activity study of nonivamide and Nordihydrocapsaicin compounds as anti-inflammatories. Florea J Biol Learn. 2021 Nov 25;8(2):82. doi: 10.25273/florea.v8i2.9983.32.

Bare Y, Maulidi A, Sari DR, Tiring SS. In silico study predicts the potential of 6-gingerol as an inhibitor of c-Jun N-terminal kinases (JNK). J Math Sci Netw S. 2019 Dec 31;1(2):59-63. doi: 10.36873/jjms.v1i2.211.33.

Bare Y, Helvina M, Krisnamurti GC, SM. The potential role of 6-gingerol and 6-shogaol as ACE inhibitors in silico study. Bio. 2020;8(2):210. doi: 10.24252/bio.v8i2.15704.

Sari DR, Safitri A, Cairns JR, Fatchiyah. Anti-apoptotic activity of anthocyanins has potential to inhibit caspase-3 signaling. J Trop Life Science. 2020;10(1):15-25. doi: 10.11594/jtls.10.01.03.

Sari D, Safitri A, Cairns J, Fatchiyah F. Virtual screening of black rice anthocyanins as antiobesity through inhibiting TLR4 and JNK pathway. J Phys.: Conf Ser. 2020 Oct 1;1665(1):012024. doi: 10.1088/1742-6596/1665/1/012024.

Krisnamurti GC. Capsaicinoids from capsicum annuum as an alternative FabH inhibitor of mycobacterium tuberculosis: in silico study. Makara J Sci. 2021 Dec 30;25(4). doi: 10.7454/mss.v25i4.1248.

Sedov IA, Stolov MA, Solomonov BN. Solvophobic effects and relationships between the Gibbs energy and enthalpy for the solvation process. J Phys Org Chem. 2011 Nov 14;24(11):1088-94. doi: 10.1002/poc.1859.

Wang X, Liu Y, Xu W, Jia L, Chi D, Yu J. Irinotecan and berberine co-delivery liposomes showed improved efficacy and reduced intestinal toxicity compared with Onivyde for pancreatic cancer. Drug Deliv Transl Res. 2021 Oct 15;11(5):2186-97. doi: 10.1007/s13346-020-00884-4, PMID 33452654.

Mathew C, Lal N, SL, TRA, Varkey J. Antioxidant, anticancer and molecular docking studies of novel 5-benzylidene substituted rhodanine derivatives. Int J Pharm Pharm Sci. 2023 Jul 1;15(7):7-19. doi: 10.22159/ijpps.2023v15i7.47421.

Ta GC, Mokhtar MB, Peterson PJ, Yahaya NB. A comparison of mandatory and voluntary approaches to the implementation of globally harmonized system of classification and labelling of chemicals (GHS) in the management of hazardous chemicals. Ind Health. 2011;49(6):765-73. doi: 10.2486/indhealth.ms1258, PMID 22020020.

Pratt I. Global harmonisation of classification and labelling of hazardous chemicals. Toxicol Lett. 2002 Mar;128(1-3):5-15. doi: 10.1016/s0378-4274(01)00529-x, PMID 11869813.

Neag MA, Mocan A, Echeverria J, Pop RM, Bocsan CI, Crişan G. Berberine: botanical occurrence, traditional uses, extraction methods, and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol. 2018 Aug 21;9:557. doi: 10.3389/fphar.2018.00557, PMID 30186157, PMCID PMC6111450.

Abushouk AI, Salem AM, Abdel Daim MM. Berberis vulgaris for cardiovascular disorders: a scoping literature review. Iran J Basic Med Sci. 2017;20(5):503-10. doi: 10.22038/ IJBMS.2017.8674, PMID 28656085, PMCID PMC5478778.

Kysenius K, Brunello CA, Huttunen HJ. Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury. Plos One. 2014 Sep 5;9(9):e107129. doi: 10.1371/journal.pone.0107129, PMID 25192195, PMCID PMC4156429.

Inbaraj JJ, Kukielczak BM, Bilski P, Sandvik SL, Chignell CF. Photochemistry and photocytotoxicity of alkaloids from goldenseal (Hydrastis canadensis L.) 1. berberine. Chem Res Toxicol. 2001 Nov 1;14(11):1529-34. doi: 10.1021/tx0155247, PMID 11712911.

Pinto Garcia L, Efferth T, Torres A, Hoheisel JD, Youns M. Berberine inhibits cell growth and mediates caspase-independent cell death in human pancreatic cancer cells. Planta Med. 2010 Aug 7;76(11):1155-61. doi: 10.1055/s-0030-1249931, PMID 20455200.

Ming M, Sinnett Smith J, Wang J, Soares HP, Young SH, Eibl G. Dose-dependent AMPK-dependent and independent mechanisms of berberine and metformin inhibition of mTORC1, ERK, DNA synthesis and proliferation in pancreatic cancer cells. Plos One. 2014 Dec 10;9(12):e114573. doi: 10.1371/journal.pone.0114573, PMID 25493642, PMCID PMC4262417.

Park SH, Sung JH, Chung N. Berberine diminishes side population and down-regulates stem cell-associated genes in the pancreatic cancer cell lines PANC-1 and MIA PaCa-2. Mol Cell Biochem. 2014 Sep 4;394(1-2):209-15. doi: 10.1007/s11010-014-2096-1, PMID 24894821.

Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res. 2015 Feb;48(2):111-9. doi: 10.1590/1414-431X20144293, PMID 25517919. PMCID PMC4321216.

Agnarelli A, Natali M, Garcia Gil M, Pesi R, Tozzi MG, Ippolito C. Cell-specific pattern of berberine pleiotropic effects on different human cell lines. Sci Rep. 2018 Jul 13;8(1):10599. doi: 10.1038/s41598-018-28952-3, PMID 30006630, PMCID PMC6045596.

Liu J, Luo X, Guo R, Jing W, Lu H. Cell metabolomics reveals berberine-inhibited pancreatic cancer cell viability and metastasis by regulating citrate metabolism. J Proteome Res. 2020 Sep 4;19(9):3825-36. doi: 10.1021/acs.jproteome.0c00394, PMID 32692565.

Tian W, Hao H, Chu M, Gong J, Li W, Fang Y. Berberine suppresses lung metastasis of cancer via inhibiting endothelial transforming growth factor beta receptor 1. Front Pharmacol. 2022 Jun 16;13:917827. doi: 10.3389/fphar.2022.917827, PMID 35784732, PMCID PMC9243563.

Liu M, Yang Y, Kang W, Liu Y, Tao X, Li X. Berberine inhibits pancreatic intraepithelial neoplasia by inhibiting glycolysis via the adenosine monophosphate -activated protein kinase pathway. Eur J Pharmacol. 2022 Jan;915:174680. doi: 10.1016/j.ejphar.2021.174680, PMID 34890544.

Fang X, Miao XL, Liu JL, Zhang DW, Wang M, Zhao DD. Berberine induces cell apoptosis through cytochrome C/Apoptotic protease-activating factor 1/caspase-3 and apoptosis-inducing factor pathway in mouse insulinoma cells. Chin J Integr Med. 2019 Nov 4;25(11):853-60. doi: 10.1007/s11655-015-2280-5, PMID 26142340.