Original Article IN SILICO MOLECULAR DOCKING OF XANTHONE DERIVATIVES AS CYCLOOXYGENASE-2 INHIBITOR AGENTS ISNATIN MILADIYAH 1 , JUMINA JUMINA 2 , SOFIA MUBARIKA HARYANA 3 , MUSTOFA MUSTOFA 4 1 Pharmacology Department, Faculty of Medicine, Islamic University of Indonesia, Yogyakarta, 2 Chemistry Department, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Yogyakarta, 3 Histology and Cell Biology Department, Faculty of Medicine, Gadjah Mada University, Yogyakarta, 4 Pharmacology and Therapeutic Department, Faculty of Medicine, Gadjah Mada University, Yogyakarta Email: isnatin@gmail.com Received: 26 Sep 2016 Revised and Accepted: 17 Jan 2017 ABSTRACT Objective: To demonstrate the potential ofdifferent xanthone derivatives as cyclooxygenase-2 (COX-2) inhibitor agents and their selectivity against cycloooxygenase-1 (COX-1) and COX-2 using molecular simulation. Methods: Nine novel xanthone derivatives (compounds A-I) were employed to dock against protein COX-2 (Protein Data Bank/PDB ID: 1CX2) and COX-1 (PDB ID: 3N8Z). Celecoxib, a selective COX-2 inhibitor, was chosen as a control compound. The free binding energy produced by the docking was scored using Protein-Ligand Ant System (PLANTS) and the hydrogen bonds (H-bonds) between ligands and enzymes were visualised using Pymol. Results: Molecular docking studies revealed that celecoxib docked to the active site of COX-2 enzyme, but not to COX-1; where as xanthone derivatives docked to the active site of both COX-2 and COX-1. Free binding energy of xanthone derivatives ranged between-73, 57 to-79,18 and between-73,06 to-79,25 against COX-2 and COX-1, respectively, and-78,13 against celecoxib. H-bonds in the molecule of xanthone derivatives and COX-2 protein were found in amino acid residues Arg 120 , Tyr 355 , Tyr 385 , and Ser 353 . There was an insignificant difference between the free binding energyof xanthone derivatives against COX-2 and against COX-1, suggesting that their inhibition was non-selective. Conclusion: In conclusion, in silico studies showed that xanthone derivatives could be effective as potential inhibitors against COX-2, although they are not selective. Keywords: Xanthones, Molecular docking, Anticancer, COX-2, Selectivity © 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijpps.2017v9i3.15382 INTRODUCTION The cyclooxygenase (COX) enzyme plays an important role in the production of prostaglandin from arachidonic acid, which is involved in various processes in the body, including inflammation, pain, and hyperpyrexia [1]. It is widely known that COX has two isoforms, namely COX-1 and COX-2. COX-1 is a constitutive part of the body thatmaintains the normal function of the gastrointestinal organs, the kidneys, and platelets, while COX-2 is an inducible enzyme that is primarily expressed by various pro-inflammatory cytokines, lipopolysaccharides, mitogens, and oncogens [2]. When COX-1 is inhibited, the inflammation process will decrease. Impairments in gastrointestinal mucous protection,as well asthe normal functions of the kidneys and platelets, along with other side effects,may occur [1]. Clinical data shows that, although COX-2 plays a role in the repairment of injury, excessive expression of this enzyme will promotevarious pathological processes, including carcinogenesis and cancer growth [3]. COX-2 enzymes are found to be highly expressed in a number of inflammatory processes and tumours, such as inflammatory bowel disease (IBD) and colon cancer, whereas it is minimal or undetected at the normal colon cell [4]. This iswhy research on new anti-inflammatory drugs has been focusing on the identification of compounds with selective activity against COX-2 in preventing the inflammation process. A number of studies show that the inflammation process is involved in carcinogenesis. The immune system, cytokines, chemokines, and transcription factors are directly associated with malignancy, which together form an “orchestra” in the pathogenesis of cancer. Immune cells in the microenvironment with inflammation stimulate the production of cytokines and chemokines. These will activate transcription factors responsible for spreading the tumour (mainly nuclear factor kappa B/NFκB and signal transducer and activator of transcription 3/STAT3) and stimulate other pro-inflammatory cytokines [5]. Therefore, inflammation can be considered as an initial form of tumour progression that may develop into a true cancer [6]. The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) in chemoprevention of cancer has proven capable in reducing incidences ofcancer and preventing mortality in some cancers, such as cancer ofthe colorectal [7], stomach [8], lung [9], breast [10], lymphatic tissue(Hodgkin lymphoma) [11], pancreas, oesophagus, kidney and bladder [12]. Aspirin and other NSAIDs act as antitumors by shifting the balance of Bax/Bcl-2 and activating a number of caspases [13], as antiplatelet drugs [14], by inhibiting the signalling process of NF-κB [16], as anti-angiogenesis drugs [17], and by inducing Rac1 gene involved in the apoptosis [18]. Selective COX-2 inhibitors were formerly developed as an anti- inflammatory drug with fewer gastrointestinal side effects when compared to COX-1 [18]. In long-term use, some COX-2 inhibitors (rofecoxib and valdecoxib) increase the risk of heart attacks and strokes; thus, they were withdrawn from the market. Currently, celecoxib is the only COX-2 selective inhibitor available in the market [19]. There is a rising urge to develop a new selective COX-2 inhibitor with fewer side effects through a more effective and efficient drug discovery process. A method to investigate a more effective and efficient new drug is using molecular docking. This is a part of molecular modelling that predicts interaction orientations (conformations) between two molecules precisely, as shown by the formation of a stable complex. The most preferred orientation (the best conformer) is indicated by the lowest binding energy and is associated with the strongest interaction. This method allows us to explore and investigate many drugs for the same receptor atthe same time. The drug with a better interaction between a ligand and a receptor will be chosen for use in laboratory experiments, and it saves resources and is less time-consuming [20]. International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 9, Issue 3, 2017