Vol 10, Issue 8, 2017 Online - 2455-3891 Print - 0974-2441 MOLECULAR DOCKING OF ANTIMYCIN A 3 ANALOGS AND ITS AROMATIC SEGMENTS AS INHIBITORS OF APOPTOSIS PROTEIN MARKER BCL-XL AND MCL-1 ADE ARSIANTI*, FADILAH FADILAH, LINDA ERLINA, RAFIKA INDAH PARAMITA Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6 Jakarta 10430, Indonesia. Email: arsi_ade2002@yahoo.com Received: 27 February 2017, Revised and Accepted: 27 April 2017 ABSTRACT Objective: Apoptosis is an important cellular process that causes the death of damaged cells. Its malfunction can lead to cancer development and poor response to conventional chemotherapy. Cellular proteins from the B-cell lymphoma 2 (BCL-2) family are crucial for apoptosis. Breast cancer is the most commonly diagnosed cancer among women worldwide. The aim of this work was to design using in silico docking antimycin A 3 , antimycin analogs, and its aromatic segments as inhibitors of Bcl-xl and Mcl-1. Methods: In silico molecular docking approach has been utilized to find the potential anticancer from antimycin A 3 analogs and its aromatic segments. Antimycin A 3 analogs and its aromatic segments were modeled into three-dimensional (3D) structures using Marvin Sketch. Based on Protein Data Bank, 3ZLN for Bcl-xl, and 5IEZ for Mcl-1 were selected as apoptosis protein marker from BCL-2 family. Geometry optimization and minimization of energy 3D structure of antimycin A 3 analogs and segments (ligands) using the AutoDock software. Docking process and amino acid residue analysis were executed using AutoDock software. The best docking score was shown by the lowest binding energy and also checked with Lipinski rule of five. Results: In silico molecular docking showed antimycin A 3 analogs, amide 5 and aromatic segment 14 have the best interaction and activity for Bcl-xl receptor inhibition. Moreover, amide 5 and segment 15 showed the best interaction and activity for Mcl-1 receptor inhibition. Conclusion: Our results clearly demonstrate that amide 5, segment 14, and segment 15 of antimycin A 3 analog have a strong inhibitory activity against Bcl-xl and Mcl-1, and should be further developed as a promising candidate for the new anti-apoptosis agents. Keywords: Molecular docking, Antimycin A 3 analog, Apoptosis, Bcl-xl, Mcl-1, Breast cancer. INTRODUCTION Apoptosis is a key for a cellular process that causes the death of damaged cells [1]. Malfunction of apoptosis can trigger to cancer development and poor response to conventional chemotherapy [2]. Cellular proteins from the B-cell lymphoma 2 (BCL-2) family are important for apoptosis [3,4]. Understanding their interactions is vital for anticancer drug design [5]. Proteins from the BCL-2 family can be either was (pro-apoptotic) or prosurvival (anti-apoptotic). Anti- apoptotic proteins such as BCL-2, BCL-xl, and MCL-1, share homology in three to four conserved BH peptide domains, namely, BH1, BH2, BH3, and BH4 [6,7]. Pro-apoptotic proteins such as BAX, BAK, BIM, BAD, and BID, share homology only in the BH3 domain [8]. The BH3 region is responsible for mediating the interactions with anti-apoptotic proteins and is related to the ability of a protein to promote programed cell death [9]. The structures of BCL-2 and BCL-xl are composed of eight α-helices with a hydrophobic groove on the protein surface containing all the four (BH1, BH2, BH3, and BH4) conserved domains [10,11]. MCL-1 shows structural similarity with BCL-2 and BCL-xl except for the absence of BH4 domain at the N-terminal [11]. After receiving the appropriate signals, pro-apoptotic proteins bind to anti-apoptotic proteins via BH3 domains on their surfaces. When cytochrome C is released from the mitochondrial inner membrane space, the apoptosis process is initiated [12]. Overexpression of anti-apoptotic BCL-2 family proteins prevents the release of cytochrome C from mitochondria and is responsible for many types of human cancers such as breast and prostate cancer [13,14]. Breast cancer is the most commonly diagnosed cancer among women worldwide. Approximately 30% of the women diagnosed with the early-stage disease in turn progress to metastatic breast cancer, for which treatment with anti-breast cancer therapeutic agents is needed. Although many current anti-breast cancer therapies can alter tumor growth, in most cases the effect is not long lasting, and commonly develop resistance against anticancer agents used which causes around 50% of all treated patients will relapse [15-17]. This fact indicated that the search for new agents which more effective, safe, and potentially extend the survival of breast cancer patients are needed. Antimycin A 3 , a nine-membered dilactone which isolated from Streptomyces sp., is an active agent that inhibits the electron transfer activity of ubiquinol-cytochrome C oxidoreductase and prevents the growth of human cancer cells [15]. Antimycin A 3 was also found to induce apoptosis of cancer cells by selectively killing the cancer cells that expressed high levels of anti-apoptotic Bcl-2 and Bcl-xl [18-20]. Bcl-2 is known to be over-expressed in 70% of breast cancer cells [21], therefore, it is reasonable to expect antimycin A 3 and its analogs to induce apoptosis of those cells. In 2012, we have succeeded to synthesize novel polyhydroxylated 18-membered analog of antimycin A 3 which demonstrated strong anticancer activity against HeLa cells, breast MDA-MB-231 cells, and prostate PC-3 cells [22]. In 2015, we reported the synthesis of novel open-chain analog of antimycin A 3 that showed anticolorectal cancer activity against HCT-116 cells [23]. In this research, we focused on © 2017 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/ajpcr.2017.v10i8.18165 Research Article