• SALBIAH RIDWAN Department of Pharmacology, Faculty of Pharmacy, Universitas Indonesia, Gedung Fakultas Farmasi Kampus UI Depok 16424, Indonesia
  • LINDA ERLINA Department of Medicinal Chemistry, Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya no.6, Indonesia
  • ANTON BAHTIAR Department of Pharmacology, Faculty of Pharmacy, Universitas Indonesia, Gedung Fakultas Farmasi Kampus UI Depok 16424, Indonesia
  • DEWI SUKMAWATI Department of Histology, Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya no.6, Indonesia



colon cancer, Wnt/β-catenin signaling pathway, Protein-Protein Interaction Network, Molecular Docking


Objective: We aimed to predict the PPI network and in silico analysis of a drug that can potentially inhibit colon cancer, specifically in the Wnt/β-catenin signaling pathway, based on pharmacophore modeling and molecular docking.

Methods: Target genes involved in colon development were screened for specific genes in the Wnt/b-catenin signaling pathway. Tissue construction and possible signaling pathways were analyzed using protein-protein interactions. Genes with significant centrality and best-grade values ​​were made to feature pharmacophore models and their suitability for potential drugs. Validation was carried out using the molecular docking method for interaction with the best Hits.

Results: Protein-Protein Interaction Network (PPI) revealed BTNNB1, TP53, AXIN, FZD-8, and CDK1 as potential critical targets in the Wnt/β-catenin signaling pathway and from the suitability of pharmacophore features obtained 27 drugs as the best Hit compounds. The therapeutic effects of the drugs we found were shown to be related to the synergistic activity (multitarget and multi-path). GO enrichment analysis revealed 36 GO entries, including 11 biological processes, 10 cellular components, and 15 molecular functions. Molecular docking experiments confirmed the correlation between three drugs (Clofazimine, Closantel, and Sulindac) with the best binding to 4 target proteins (AXIN1, TP53, CDK1, and FZD-8).

Conclusion: In this study, we found a potent drug that can inhibit colon cancer disease in the Wnt/β-catenin signaling pathway and an essential target protein responsible for the efficacy of colon cancer treatment, providing a theoretical basis for further research.


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Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.

Church J. Molecular genetics of colorectal cancer. Semin Colon Rectal Surg [Internet]. 2016;27(4):172–5. Available from:

Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet [Internet]. 2019;394(10207):1467–80. Available from:

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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):209–49.

Pangribowo S. Beban Kanker di Indonesia. Pus Data Dan Inf Kesehat Kementeri Kesehat RI. 2019;1–16.

Koncina E, Haan S, Rauh S, Letellier E. Prognostic and predictive molecular biomarkers for colorectal cancer: Updates and challenges. Cancers (Basel). 2020;12(2):1–25.

Salik B, Yi H, Hassan N, Santiappillai N, Vick B, Connerty P, et al. Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. Cancer Cell [Internet]. 2020;38(2):263-278.e6. Available from:

Soleas JP, D’Arcangelo E, Huang L, Karoubi G, Nostro MC, McGuigan AP, et al. Assembly of lung progenitors into developmentally-inspired geometry drives differentiation via cellular tension. Biomaterials [Internet]. 2020;254(May):120128. Available from:

Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol [Internet]. 2020;13(1):1–16. Available from:

Xie YH, Chen YX, Fang JY. A comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther [Internet]. 2020;5(1). Available from:

Safran M, Rosen N, Twik M, BarShir R, Stein TI, Dahary D, et al. The GeneCards Suite. Pract Guide to Life Sci Databases. 2021;27–56.

Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinforma. 2016;2016(June):1.30.1-1.30.33.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A Software Environment for Integrated Models. Genome Res [Internet]. 2003;13(22):426. Available from:

Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, et al. STRING 8 - A global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009;37(SUPPL. 1):412–6.

Kuhn M, von Mering C, Campillos M, Jensen LJ, Bork P. STITCH: Interaction networks of chemicals and proteins. Nucleic Acids Res. 2008;36(SUPPL. 1):684–8.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acid Res. 2021;47(1).

Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model. 2005;45(1):160–9.

Kessler D, Mayer M, Zahn SK, Zeeb M, Wöhrle S, Bergner A, et al. Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods. ChemMedChem. 2021;16(9):1420–4.

Fugel W, Oberholzer AE, Gschloessl B, Dzikowski R, Pressburger N, Preu L, et al. fugel2013HYDE. J Med Chem. 2012;56(1).

Dai Y, Zhang A, Shan S, Gong Z, Zhou Z. Structural basis for recognizing 53BP1 tandem Tudor domain by TIRR. Nat Commun [Internet]. 2018;9(1). Available from:

Madej T, Lanczycki CJ, Zhang D, Thiessen PA, Geer RC, Marchler-Bauer A, et al. MMDB, and VAST+: Tracking structural similarities between macromolecular complexes. Nucleic Acids Res. 2014;42(D1):297–303.

Zhao Y, Ren J, Hillier J, Lu W, Jones EY. Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8. J Med Chem. 2020;63(6):3252–60.

Scott DE, Ehebauer MT, Pukala T, Marsh M, Blundell T, Venkitaraman A, et al. Using a Fragment-Based Approach To Target Protein-Protein Interactions. Chembiochem. 2013;14(3).

Dassault Systèmes BIOVIA. Discovery Studio Modeling Environment, Release 2021. Dassault Systèmes: San Diego, CA, USA; 2021.

Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015;1263(January 2015):243–50.

Chen C, Wang T, Wu F, Huang W, He G, Ouyang L, et al. Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity. Drug Des Devel Ther. 2014;8:1195–210.

Zappavigna S, Cossu AM, Grimaldi A, Bocchetti M, Ferraro GA, Nicoletti GF, et al. Anti-inflammatory drugs as anticancer agents. Int J Mol Sci. 2020;21(7):1–29.

Durusu İZ, Hüsnügil HH, Ataş H, Biber A, Gerekçi S, Güleç EA, et al. Anti-cancer effect of clofazimine as a single agent and in combination with cisplatin on U266 multiple myeloma cell line. Leuk Res. 2017;55:33–40.

Nowak-Sliwinska P, Scapozza L, Altaba AR i. Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer. Biochim Biophys Acta - Rev Cancer [Internet]. 2019;1871(2):434–54. Available from:

Zhao R, Coker OO, Wu J, Zhou Y, Zhao L, Nakatsu G, et al. Aspirin Reduces Colorectal Tumor Development in Mice, and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects. Gastroenterology [Internet]. 2020;159(3):969-983.e4. Available from:

Koveitypour Z, Panahi F, Vakilian M, Peymani M, Seyed Forootan F, Nasr Esfahani MH, et al. Signaling pathways involved in colorectal cancer progression. Cell Biosci [Internet]. 2019;9(1):1–14. Available from:

Zhang X, Wang L, Qu Y. Targeting the β-catenin signaling for cancer therapy. Pharmacol Res. 2020;160(September 2019).

Nazemalhosseini Mojarad E, Kashfi SMH, Mirtalebi H, Almasi S, Chaleshi V, Kishani Farahani R, et al. Prognostic Significance of Nuclear β-Catenin Expression in Patients with Colorectal Cancer from Iran. Iran Red Crescent Med J. 2015;17(7).

Zhao H, Ming T, Tang S, Ren S, Yang H, Liu M, et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Mol Cancer [Internet]. 2022;21(1):1–34. Available from:

Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15(6):1–10.

Li J, Wang Y, Wang X, Yang Q. CDK1 and CDC20 overexpression in colorectal cancer is associated with poor prognosis: Evidence from integrated bioinformatics analysis. World J Surg Oncol. 2020;18(1):1–11.

Dong S, Huang F, Zhang H, Chen Q. in Tumor Tissues Predicts Poor Survival in Pancreatic Ductal Adenocarcinoma. 2019;0:1–10.

Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, et al. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics. 2018;8(14):3737–50.

Huang J, Chen P, Liu K, Liu J, Zhou B, Wu R, et al. CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer. Gut. 2021;70(5):890–9.

Zhu Y, Li K, Zhang J, Wang L, Sheng L, Yan L. Inhibition of cdk1 reverses the resistance of 5-fu in colorectal cancer. Cancer Manag Res. 2020;12:11271–83.

Williams DS, Mouradov D, Browne C, Palmieri M, Elliott MJ, Nightingale R, et al. Overexpression of TP53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer. Mod Pathol [Internet]. 2020;33(3):483–95. Available from:

Fearon RE, Vogelstein B. A Genetic Model for Colorectal Tumorgenesis. G Ital Cardiol. 1990;19(2):170–2.

Alrefaei AF. Frizzled receptors (FZD) play multiple cellular roles in development, in diseases, and as potential therapeutic targets [Internet]. Vol. 33, Journal of King Saud University - Science. The Author(s); 2021. p. 101613. Available from:

Murillo-Garzón V, Gorroño-Etxebarria I, Åkerfelt M, Puustinen MC, Sistonen L, Nees M, et al. Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer. Nat Commun [Internet]. 2018;9(1). Available from:

Kurnit KC, Kim GN, Fellman BM, Urbauer DL, Mills GB, Zhang W, et al. CTNNB1 (beta-catenin) mutation identifies low-grade, early-stage endometrial cancer patients at increased risk of recurrence. Mod Pathol [Internet]. 2017;30(7):1032–41. Available from:

Santos VS, Lago NM, Garcia CP, Garcia AP, Apricio LMA. Signaling pathways in CRC. In: Sierra AP, editor. Foundations of Colorectal Cancer. 1st ed. Academic Press Inc.; 2022. p. 519–28.

Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights [Internet]. Vol. 58, Seminars in Cancer Biology. Elsevier; 2019. p. 65–79. Available from:



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