Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Yehezkiel Steven Kurniawan(1), Ervan Yudha(2), Gerry Nugraha(3), Nela Fatmasari(4), Harno Dwi Pranowo(5), Jumina Jumina(6*), Eti Nurwening Sholikhah(7)

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(3) Pharmacy, STIKES ‘Aisyiyah, Jl. Kol. H. Burlian No. 32 A, Palembang 30961, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(6) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(7) Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(*) Corresponding Author


Epidermal growth factor receptor (EGFR) is found to be overexpressed in cancer cells as it controls angiogenesis, cell signaling, and proliferation mechanisms. Therefore, EGFR has been known as a common target for the initial screening of new anticancer agents. Either xanthone or chalcone has been evaluated as the anticancer agents, and their activity strongly depends on the type and position of the attached functional group. Therefore, molecular hybridization between xanthone and chalcone could yield novel anticancer agents through the EGFR inhibition mechanism. Herein, a series of xanthone-chalcone derivatives with hydrogen-bond-acceptor or hydrogen-bond-donor substituents at ortho, meta, and para positions was evaluated as the EGFR inhibitor. Thirty-seven xanthone-chalcones were designed and docked in the active site of EGFR. Compared to the native ligand, pristine xanthone-chalcone gave a 1.215× stronger binding energy and a 13.97× lower binding constant. Compound 3SH was found to be the most promising candidate due to its strongest binding energy (−9.71 kcal/mol) and the lowest binding constant (0.08 µM). Furthermore, molecular dynamic studies demonstrated that complex EGFR-3SH was stable for 100 ns simulation. These in silico investigations show that the xanthone-chalcone derivative is a promising novel anticancer agent to be examined through in vitro and in vivo assays.


chalcone; xanthone; EGFR; molecular docking; molecular dynamics


[1] Siegel, R.L., Miller, K.D., Fuchs, H.E., and Jemal, A., 2021, Cancer statistics, 2021, Ca-Cancer J. Clin., 71 (1), 7–33.

[2] Pulcini, R., D’Agostino, S., Dolci, M., Bissioli, A., Caporaso, L., and Iarussi, F., 2022, The Impact of COVID-19 on oral cancer diagnosis: A systematic review, J. Multidiscip. Appl. Nat. Sci., 2 (2), 65–69.

[3] Chopra, B., and Dhingra, A.K., 2021, Natural products: A lead for drug discovery and development, Phytother. Res., 35 (9), 4660–4702.

[4] Saldívar-González, F.I., Aldas-Bulos, V.D., Medina-Franco, J.L., and Plisson, F., 2022, Natural product drug discovery in the artificial intelligence era, Chem. Sci., 13 (6), 1526–1546.

[5] Husni, A., Gazali, M., Nurjanah, N., Syafitri, R., Matin, A., and Zuriat, Z., Cytotoxic activity of green seaweed Halimeda tuna methanolic extract against lung cancer cells, J. Multidiscip. Appl. Nat. Sci., 10.47352/jmans.2774-3047.172.

[6] Rasyid, H., Purwono, B., Hofer, T.S., and Pranowo, H.D., 2019, Hydrogen bond stability of quinazoline derivatives compounds in complex against EGFR using molecular dynamics simulation, Indones. J. Chem., 19 (2), 461–469.

[7] Rasyid, H., Purwono, B., and Pranowo, H.D., 2021, Design of new quinazoline derivative as EGFR (epidermal growth factor receptor) inhibitor through molecular docking and dynamics simulation, Indones. J. Chem., 21 (1), 201–211.

[8] Ahmeed, N., Erlista, G.P., Raharjo, T.J., Swasono, R.T., and Raharjo, S., 2023, Anticancer activity of venom protein hydrolysis fraction of equatorial spitting cobra (Naja sumatrana), Indones. J. Chem., 23 (2), 510–522.

[9] Hassanpour, S.H., and Dehghani, M., 2017, Review of cancer from perspective of molecular, J. Cancer Res. Pract., 4 (4), 127–129.

[10] Lee, H.S., Jo, S., Lim, H.S., and Im, W., 2012, Application of binding free energy calculations to prediction of binding modes and affinities of MDM2 and MDMX inhibitors, J. Chem. Inf. Model., 52 (7), 1821–1832.

[11] Lee, S., Kim, J., Duggirala, K.B., Go, A., Shin, I., Cho, B.C., Choi, G., Chae, C.H., and Lee, K., 2018, Allosteric inhibitor TREA-0236 containing non-hydrolysable quinazoline-4-one for EGFR T790M/C797S mutants inhibition, Bull. Korean Chem. Soc., 39 (7), 895–898.

[12] Duggirala, K.B., Choe, H., Jeon, B.U., Jung, M.E., Go, A., Lim, B., Park, C., Yoon, J., Chae, C.H., Cho, B.C., Choi, G., and Lee, K., 2019, Identification of TRE-130 as reversible inhibitor of Pan-EGFR mutants while sparing EGFR wild-type activity, Bull. Korean Chem. Soc., 40 (12), 1222–1225.

[13] Uribe, M.L., Marocco, I., and Yarden, Y., 2021, EGFR in cancer: Signaling mechanisms, drugs, and acquired resistance, Cancers, 13 (11), 2748.

[14] Sudhakar, D.R., Kalaiarasan, P., and Subbarao, N., 2016, Docking and molecular dynamics simulation study of EGFR1 with EGF like peptides to understand molecular interactions, Mol. BioSyst., 12 (6), 1987–1995.

[15] Stamos, J., Sliwkowski, M.X., and Eigenbrot, C., 2002, Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor, J. Biol. Chem., 277 (48), 46265–46272.

[16] Kim, D.K., Kim, Y.S., Kim, C.S., and Lee, N.K., 2021, Method for the rapid screening of drug candidates using single-protein tracking in a living cell, Bull. Korean Chem. Soc., 42 (3), 393–397.

[17] Choe, H., Jeon, B.U., Jung, M.E., Jeon, M.K., Shin, I., Cho, B.C., Choi, G., Chae, C.H., and Lee, K., 2017, Structure-activity relationship study of 2,4-dianilinopyrimidine containing methansulfonamide (TRE-069) as potent and selective epidermal growth factor receptor T790M/C797S mutant inhibitor for anticancer treatment, Bull. Korean Chem. Soc., 38 (11), 1353–1357.

[18] Sabe, V.T., Ntombela, T., Jhamba, L.A., Maguire, G.E.M., Govender, T., Naicker, T., and Kruger, H.G., 2021, Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review, Eur. J. Med. Chem., 224, 113705.

[19] Brogi, S., Ramalho, T.C., Kuca, K., Medina-Franco, J.L., and Valko, M., 2020, Editorial: In silico methods for drug design and discovery, Front. Chem., 8, 612.

[20] Kurniawan, Y.S., Indriani, T., Amrulloh, H., Adi, L.C., Imawan, A.C., and Priyangga, K.T.A., 2023, The journey of natural products: From isolation stage to drugs approval in clinical trials, Bioactivities, 1 (2), 43–60.

[21] Pagadala, N.S., Syed, K., and Tuszynski, J., 2017, Software for molecular docking: A review, Biophys. Rev., 9 (2), 91–102.

[22] Hospital, A., Goñi, J.R., Orozco, M., and Gelpi, J., 2015, Molecular dynamics simulations: Advances and applications, Adv. Appl. Bioinf. Chem., 8, 37–47.

[23] Pinto, M.M.M., Palmeira, A., Fernandes, C., Resende, D.I.S.P., Sousa, E., Cidade, H., Tiritan, M.E., Correia-da-Silva, M., and Cravo, S., 2021, From natural products to new synthetic small molecules: A journey through the world of xanthones, Molecules, 26 (2), 431.

[24] Resende, D.I.S.P., Durães, F., Maia, M., Sousa, E., and Pinto, M.M.M., 2020, Recent advances in the synthesis of xanthones and azaxanthones, Org. Chem. Front., 7 (9), 3027–3066.

[25] Wairata, J., Sukandar, E.R., Fadlan, A., Purnomo, A.S., Taher, M., and Ersam, T., 2021, Evaluation of the antioxidant, antidiabetic, and antiplasmodial activities of xanthones isolated from Garcinia forbesii and their in silico studies, Biomedicines, 9 (10), 1380.

[26] Cidade, H., Rocha, V., Palmeira, A., Marques, C., Tiritan, M.E., Ferreira, H., Lobo, J.S., Almeida, I.F., Sousa, M.E., and Pinto, M., 2020, In silico and in vitro antioxidant and cytotoxicity evaluation of oxygenated xanthone derivatives, Arabian J. Chem., 13 (1), 17–26.

[27] Singh, A., Kaur, N., Sharma, S., and Bedi, P.M.S., 2016, Recent progress in biologically active xanthones, J. Chem. Pharm. Res., 8 (1), 75–131.

[28] Kurniawan, Y.S., Priyangga, K.T.A., Jumina, J., Pranowo, H.D., Sholikhah, E.N., Zulkarnain, A.K., Fatimi, H.A., and Julianus, J., 2021, An update on the anticancer activity of xanthone derivatives: A review, Pharmaceuticals, 14 (11), 1144.

[29] Gao, F., Huang, G., and Xiao, J., 2020, Chalcone hybrids as potential anticancer agents: Current development, mechanism of action, and structure-activity relationship, Med. Res. Rev., 40 (5), 2049–2084.

[30] Rammohan, A., Reddy, J.S., Sravya, G., Rao, C.N., and Zyryanov, G.V., 2020, Chalcone synthesis, properties and medicinal applications: A review, Environ. Chem. Lett., 18 (2), 433–458.

[31] Salehi, B., Quispe, C., Chamkhi, I., El Omari, N., Balahbib, A., Sharifi-Rad, J., Bouyahya, A., Akram, M., Iqbal, M., Docea, A.O., Caruntu, C., Leyva-Gómez, G., Dey, A., Martorell, M., Calina, D., López, V., and Les, F., 2021, Pharmacological properties of chalcones: A review of preclinical including molecular mechanisms and clinical evidence, Front. Pharmacol., 11, 592654.

[32] Leite, F.F., de Sousa, N.F., de Oliveira, B.H.M., Duarte, G.D., Ferreira, M.D.L., Scotti, M.T., Filho, J.M.B., Rodrigues, L.C., de Moura, R.O., Mendonça-Junior, F.J.B., and Scotti, L., 2023, Anticancer activity of chalcones and its derivatives: Review and in silico studies, Molecules, 28 (10), 4009.

[33] Anwar, C., Prasetyo, Y.D., Matsjeh, S., Haryadi, W., Sholikhah, E.N., and Nendrowati, N., 2018, Synthesis of chalcone derivatives and their in vitro anticancer test against breast (T47D) and colon (WiDr) cancer cell line, Indones. J. Chem., 18 (1), 102–107.

[34] Suma, A.A.T., Wahyuningsih, T.D., and Mustofa, M., 2019, Efficient synthesis of chloro chalcones under ultrasound irradiation, their anticancer activities and molecular docking studies, Rasayan J. Chem., 12 (2), 502–510.

[35] Li, P.H., Jiang, H., Zhang, W.J., Li, Y.L., Zhao, M.C., Zhou, W., Zhang, L.Y., Tang, Y.D., Dong, C.Z., Huang, Z.S., Chen, H.X., and Du, Z.Y., 2018, Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers, Eur. J. Med. Chem., 145, 498–510.

[36] Zhou, W., Zhang, W., Peng, Y., Jiang, Z.H., Zhang, L., and Du, Z., 2020, Design, synthesis and anti-tumor activity of novel benzimidazole-chalcone hybrids as non-intercalative topoisomerase II catalytic inhibitors, Molecules, 25 (14), 3180.

[37] Liu, J., Zhou, F., Zhang, L., Wang, H., Zhang, J., Zhang, C., Jiang, Z., Li, Y., Liu, Z., and Chen, H., 2018, DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions, Eur. J. Med. Chem., 143, 1768–1778.

[38] Georgakopoulos, A., Kalampaliki, A.D., Gioti, K., Hamdoun, S., Giannopoulou, A.F., Efferth, T., Stravopodis, D.J., Tenta, R., Marakos, P., Pouli, N., and Kostakis, I.K., 2020, Synthesis of novel xanthone and acridone carboxamides with potent antiproliferative activities, Arabian J. Chem., 13 (11), 7953–7969.

[39] Iresha, M.R., Jumina, J., Pranowo, H.D., Sholikhah, E.N., and Hermawan, F., 2022, Synthesis, cytotoxicity evaluation and molecular docking studies of xanthyl-cinnamate derivatives as potential anticancer agents, Indones. J. Chem., 22 (5), 1407–1417.

[40] Fatmasari, N., Kurniawan, Y.S., Jumina, J., Anwar, C., Priastomo, Y., Pranowo, H.D., Zulkarnain, A.K., and Sholikhah, E.N., 2022, Synthesis and in vitro assay of hydroxyxanthones as antioxidant and anticancer agents, Sci. Rep., 12 (1), 1535.

[41] Meng, X.Y., Zhang, H.X., Mezei, M., and Cui, M, 2011, Molecular docking: A powerful approach for structure-based drug discovery, Curr. Comput.-Aided Drug Des., 7 (2), 146–157.

[42] Chabaan, I., Hafez, H., AlZaim, I., Tannous, C., Ragab, H., Hazzaa, A., Ketat, S., Ghoneim, A., Katary, M., Abd-Alhaseeb, M.M., Zouein, F.A., Albohy, A., Amer, A.N., El-Yazbi, A.F., and Belal, A.S.F., 2021, Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis, Bioorg. Chem., 113, 105035.

[43] Sun, J., Wei, Q., Zhou, Y., Wang, J., Liu, Q., and Xu, H., 2017, A systematic analysis of FDA-approved anticancer drugs, BMC Syst. Biol., 11 (5), 87.

[44] Saladi, J.S.C., Nangi, G.B.S., Chavakula, R., Karumanchi, K., and Bonige, K.B., 2023, Identification and synthesis of potential process-related impurities of trametinib: An anti-cancer drug, Chem. Pap., 77 (3), 1759–1763.

[45] Dai, Z., and Wang, Z., 2020, Photoactivable platinum-based anticancer drugs: Mode of photoactivation and mechanism of action, Molecules, 25 (21), 5167.

[46] Rappaport, J., 2017, Changes in dietary iodine explains increasing incidence of breast cancer with distant involvement in young women, J. Cancer, 8 (2), 174–177.

[47] Zhang, D., Xu, X., Li, J., Yang, X., Sun, J., Wu, Y., and Qiao, H., 2019, High iodine effects on the proliferation, apoptosis, and migration of papillary thyroid carcinoma cells as a result of autophagy induced by BRAF kinase, Biomed. Pharmacother., 120, 109476.

[48] Darbandi, A., Gavahi, M., Shirani Bidabadi, E., Kadhim, M.M., Naghsh, N., Canli, G., and Ahmed, O.S., 2022, Complexation of mercaptopurine anticancer drug with an iron-doped fullerene cage: DFT assessments of drug delivery approach, Phys. Lett. A, 448, 128318.

[49] Munshi, P.N., Lubin, M., and Bertino, J.R., 2014, 6-Thioguanine: A drug with unrealized potential for cancer therapy, Oncologist, 19 (7), 760–765.

[50] Chen, X., Jia, F., Huang, Y., Jin, Q., and Ji, J., 2022, Cancer-associated fibroblast-targeted delivery of captopril to overcome penetration obstacles for enhanced pancreatic cancer therapy, ACS Appl. Bio Mater., 5 (7), 3544–3553.

[51] Shahzadi, I., Zahoor, A.F., Tüzün, B., Mansha, A., Anjum, M.N., Rasul, A., Irfan, A., Kotwica-Mojzych, K., and Mojzych, M., 2022, Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1,2,4-triazole, PLoS One, 17 (12), e0278027.

[52] Ptaff, A.R., Beltz, J., King, E., and Ercal, N., 2020, Medicinal thiols: Current status and new perspectives, Mini-Rev. Med. Chem., 20 (6), 513–529.

[53] Dalzoppo, D., Di Paolo, V., Calderan, L., Pasut, G., Rosato, A., Caccuri, A.M., and Quintieri, L., 2017, Thiol-activated anticancer agents: The state of the art, Anti-Cancer Agents Med. Chem., 17 (1), 4–20.

[54] Sun, S., Oliveira, B.L., Jiménez-Osés, G., and Bernardes, G.J.L., 2018, Radical-mediated thiol-ene strategy: Photoactivation of thiol-containing drugs in cancer cells, Angew. Chem., Int. Ed., 57 (48), 15832–15835.

[55] Kurniawan, Y.S., Fatmasari, N., Jumina, J., Pranowo, H.D., and Sholikhah, E.N., 2023, Evaluation of the anticancer activity of hydroxyxanthones against human liver carcinoma cell line, J. Multidiscip. Appl. Nat. Sci., 10.47352/jmans.2774-3047.165.

[56] Choowongkomon, K., Sawatdichaikul, O., Songtawee, N., and Limtrakul, K., 2010, Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database, Molecules, 15 (6), 4041–4054.

[57] Almalki, F.A., Shawky, A.M., Abdalla, A.N., and Gouda, A.M., 2021, Icotinib, almonertinib, and olmutinib: A 2D similarity/docking-based study to predict the potential binding modes and interactions into EGFR, Molecules, 26 (21), 6423.

[58] Balasubramanian, P.K., Lee, Y., and Kim, Y., 2019, Identification of ligand-binding hotspot residues of CDK4 using molecular docking and molecular dynamics simulation, Bull. Korean Chem. Soc., 40 (10), 1025–1032.

[59] Nugraha, G., Pranowo, H.D., Mudasir, M., and Istyastono, E.P., 2022, Virtual target construction for discovery of human histamine H4 receptor ligands employing a structure-based virtual screening approach, Int. J. Appl. Pharm., 14 (4), 213–218.

[60] Istyastono, E.P., and Riswanto, F.D.O., 2022, Molecular dynamics simulations of the caffeic acid interactions to dipeptidyl peptidase IV, Int. J. Appl. Pharm., 14 (4), 274–278.


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