Vol. 13 | No. 4 |2626-2632| October - December | 2020 ISSN: 0974-1496 | e-ISSN: 0976-0083 | CODEN: RJCABP http://www.rasayanjournal.com http://www.rasayanjournal.co.in Rasayan J. Chem., 13(4), 2626-2632(2020) http://dx.doi.org/10.31788/ RJC.2020.1345699 DESIGN OF THIOXANTHONE DERIVATIVES AS POTENTIAL TYROSINE KINASE INHIBITOR: A MOLECULAR DOCKING STUDY F. Hermawan 1,2 , J. Jumina 1,* and H.D. Pranowo 1,2 1 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta-55281, (Yogyakarta) Indonesia 2 Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta-55281, (Yogyakarta) Indonesia *E-mail: jumina@ugm.ac.id ABSTRACT Xanthone derivatives have been well-known for their wide and outstanding bioactivity so far. However, investigation of thioxanthone derivatives and their biological activity is rarely reported. In this work, molecular docking analysis was conducted to evaluate the thioxanthone activity as a tyrosine kinase inhibitor (PDGFR, EGFR). Six thioxanthone derivatives (A-F) were optimized using Gaussian 09 with a semi-empirical method and were docked to the receptor using AutoDock4 software. The free binding energy of thioxanthone derivatives was ranging from -7.10 to -8.57 and -6.23 to -7.25 kcal mol -1 against PDGFR and EGFR. Docking result of all thioxanthone derivatives into PDGFR protein exhibited higher binding energies than that of imatinib, whereas docking result into EGFR protein of all thioxanthone derivatives (except for compound A) gave lower binding energies than that of erlotinib. Among the analyzed compounds, compound 4-iodo-1,3-dihydroxythioxanthone (F) exhibits the lowest binding energy in both tyrosine kinase inhibitors due to its ability to form a Hydrogen bond to the PDGFR receptor with the side chain of Cys673 and the EGFR receptor with the side chain Met796 amino acid residue. This result indicated that compound F has a stronger interaction in tyrosine kinase inhibitor thus promising for a new candidate of anticancer agent. Keywords: Molecular Docking, Thioxanthone, PDGFR, EGFR, AutoDock. © RASĀYAN. All rights reserved INTRODUCTION Cancer is the second serious disease that causes death in the world. In 2018, cancer is responsible for 9.6 million deaths. 1 The cancer cells attack and destroy adjacent tissues and metastasize to other parts of the human body. 2 The main problems of the cancer disease are resistance, lack of selectivity, and the occurrence of side effects to chemotherapeutic agents. 3 Hence it is highly necessary to develop new anticancer agents to solve this problem. Even though hundreds of anticancer agents have been synthesized and evaluated, their anticancer activity was not satisfied. Protein-tyrosine kinases (PTKs) are the key intermediates in cell signaling pathways that control cell growth and apoptosis. Some pathological disorders, including unregulated cell proliferation, is caused by changed functions of individual protein kinases. 4 Inhibitors of tyrosine kinase can be contemplated as a target for anti- angiogenesis and applied as a new cancer therapy model. Inhibitors of tyrosine kinase-like platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) kinase have been confirmed for their critical role in cancer. PDGFR protein is involved in the cancer cell survival and proliferation stage. PTK Inhibitors such as imatinib could block the activity of platelet-derived growth factor (PDGFR or C-Kit PTK). 5 Meanwhile for EGFR protein could influence tumor growth including metastasis, angiogenesis, proliferation, and inhibition in the apoptosis process. 6 By using tyrosine kinase inhibitors such as erlotinib, the activity of EGFR protein could be inhibited. This inhibitor interacts with the ATP binding site through Hydrogen bonding, thereby blocking signal transduction from the EGFR. 7 The systematic and scientific strategy to the discovery of novel and