MOLECULAR DOCKING OF ANTIMYCIN A3 ANALOGS AND ITS AROMATIC SEGMENTS AS INHIBITORS OF APOPTOSIS PROTEIN MARKER BCL-XL AND MCL-1

Authors

  • Ade Arsianti Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6 Jakarta 10430, Indonesia.
  • Fadilah Fadilah Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6 Jakarta 10430, Indonesia.
  • Linda Erlina Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6 Jakarta 10430, Indonesia.
  • Rafika Indah Paramita Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6 Jakarta 10430, Indonesia.

DOI:

https://doi.org/10.22159/ajpcr.2017.v10i8.18165

Keywords:

Molecular docking, Antimycin A3 analog, Apoptosis, Bcl-xl, Mcl-1, Breast cancer

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 A3, 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 A3 analogs and its aromatic segments. Antimycin A3 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 A3 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 A3 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 A3 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.

 

Downloads

Download data is not yet available.

References

Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335(6189):440-2.

Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993;81(11):3091-6.

Waksman G, editor. Proteomics and Protein-Protein Interactions: Biology, Chemistry, Bioinformatics, and Drug Design. New York, US: Springer; 2005.

Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435(7042):677-81.

Kann MG. Protein interactions and disease: Computational approaches to uncover the etiology of diseases. Brief Bioinform 2007;8(5):333-46.

Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell 2000;103(6):839-42.

Kelekar A, Thompson CB. Bcl-2-family proteins: The role of the BH3 domain in apoptosis. Trends Cell Biol 1998;8(8):324-30.

Mitchell C, Yacoub A, Hossein H, Martin AP, Bareford D, Eulitt PJ, et al. Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Inform 2010;9:169-77.

Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, et al. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 1995;14(22):5589-96.

Zhai D, Ke N, Zhang H, Ladror U, Joseph M, Eichinger A, et al. Characterization of the anti-apoptotic mechanism of Bcl-B. Biochem J 2003;376:229-36.

Michels J, Johnson PW, Packham G. Mcl-1. Int J Biochem Cell Biol 2005;37(2):267-71.

Petros AM, Olejniczak ET, Fesik SW. Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 2004;1644(2-3):83-94.

Fernández Y, Gu B, Martínez A, Torregrosa A, Sierra A. Inhibition of apoptosis in human breast cancer cells: Role in tumor progression to the metastatic state. Int J Cancer 2002;101(4):317-26.

Lebedeva I, Rando R, Ojwang J, Cossum P, Stein CA. Bcl-xL in prostate cancer cells: Effects of overexpression and down-regulation on chemosensitivity. Cancer Res 2000;60(21):6052-60.

O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist 2005;10 Suppl 3:20-9.

Lage H. Drug resistance in breast cancer. Cancer Ther 2003;1:81-91.

Rivera E, Gomez H. Chemotherapy resistance in metastatic breast cancer: The evolving role of ixabepilone. Breast Cancer Res 2010;12 Suppl 2:S2.

Kim KM, Giedt CD, Basañez G, O’Neill JW, Hill JJ, Han YH, et al. Biophysical characterization of recombinant human Bcl-2 and its interactions with an inhibitory ligand, antimycin A. Biochemistry 2001;40(16):4911-22.

Han YH. Antimycin A as a mitochondrial electron transport inhibitor prevents the growth of human lung cancer A549 cells. Oncol Rep 1994;20:104-8.

Park WH, Han YW, Kim SH, Kim SZ. An ROS generator, antimycin A, inhibits the growth of HeLa cells via apoptosis. J Cell Biochem 2007;102(1):98-109.

Liu W, Bulgaru A, Haigentz M, Stein CA, Perez-Soler R, Mani S. The BCL2-family of protein ligands as cancer drugs: The next generation of therapeutics. Curr Med Chem Anticancer Agents 2003;3(3):217-23.

Arsianti A, Tanimoto H, Morimoto T, Bahtiar A, Takeya T, Kakiuchi K. Synthesis and anticancer activity of polyhydroxylated 18-membered analogue of antimycin A3. Tetrahedron 2012;68(13):2884-91.

Arsianti A, Fadilah F, Kusmardi K, Tanimoto H, Kakiuchi K. Design, synthesis, and cytotoxicity evaluation of novel open-chain analogues of antimycin A3 as potential anti-colorectal cancer agents. Asian J Pharm Clin Res 2015;8(6):120-4.

Agarwal T, Gupta P, Asthana S, Khursheed A. In silico analysis to access the antibacterial effect of thiazides on PDFS: Molecular docking approach. Int J Pharm Pharm Sci 2014;6(6):387-91.

Dirar AI, Waddad AY, Mohamed MA, Mohamed MS, Osman WJ, Mohammed MS, et al. In silico pharmakokinetics and molecular docking of three leads isolated from Tarconanthus camphoratus. Int J Pharm Pharm Sci 2016;8(5):71-7.

Arsianti A, Fadilah, Tanimoto H, Morimoto T, Kakiuchi K. Design and molecular docking study of antimycin A3 analogues as inhibitors of anti-apoptotic Bcl-2 of breast cancer. Open J Med Chem 2014;4(4):79-86.

Fadilah F, Arsianti A, Kusmardi K, Tedjo A. Molecular docking studies of opened-chain analogues of antimycin A3 as caspases inhibitors of apoptosis in colorectal cancer. Asian J Pharm Clin Res 2016;9(3):350-2.

Arsianti A, Astuty H, Fadilah F, Bahtiar A, Tanimoto H, Kakiuchi K. Design and screening of gallic acid derivatives as inhibitors of malarial dihydrofolate reductase by in silico docking. Asian J Pharm Clin Res 2017;10(2):330-4.

Tzung SP, Kim KM, Basañez G, Giedt CD, Simon J, Zimmerberg J, et al. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 2001;3(2):183-91.

Published

01-08-2017

How to Cite

Arsianti, A., F. Fadilah, L. Erlina, and R. I. Paramita. “MOLECULAR DOCKING OF ANTIMYCIN A3 ANALOGS AND ITS AROMATIC SEGMENTS AS INHIBITORS OF APOPTOSIS PROTEIN MARKER BCL-XL AND MCL-1”. Asian Journal of Pharmaceutical and Clinical Research, vol. 10, no. 8, Aug. 2017, pp. 317-22, doi:10.22159/ajpcr.2017.v10i8.18165.

Issue

Section

Original Article(s)