MOLECULAR DOCKING, PHARMACOPHORE MODELLING, AND ADME-TOXICITY PREDICTION OF CURCUMIN ANALOG COMPOUNDS AS INFLAMMATORY INHIBITOR ON RHEUMATOID ARTHRITIS
Objective: The objective of this research was to examine the activity and cytokine inhibitory mechanism of curcumin analog compound against multiple protein targets in a patient with rheumatoid arthritis (RA) and identify the absorption, distribution, metabolism, excretion and toxicity (ADME-toxicity).
Methods: Identification was carried out by in silico through pharmacophore modelling using Ligand Scout, molecular docking using iGemDock in various protein (tumor necrosis factor alpha (TNF-Î±), interleukin-1Î² (IL-1Î²), transcription factors, signalling kinase, and cyclooxygenase enzyme) and identification of ADME-toxicity based on the physicochemical properties of the compound to simulate, predict and analyze interaction between protein and compound.
Results: The obtained results indicated that gamavuton (GVT-0) and penta-gamavuton (PGV) possessed high bioavailability with lower toxicity than curcumin. However, GVT-0, a curcumin analog, possessed high and specific inhibitory activity on tumor necrosis factor-Î± converting enzyme (TACE) and interleukin converting enzyme (ICE)/Caspase-1.
Conclusion: GVT-0 as a curcumin derivate possessed the best inhibitory activity against TNF-Î± converting enzyme and IL-1Î² converting enzyme which are the main route of inflammatory mediators in rheumatoid arthritis. In addition, GVT-0 influences less in metabolism of CYP450 enzymes, and has low toxicity.
2. Wojdasiewicz P, Poniatowski A, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Hindawi; 2014.
3. Manikandan N, Arunagirinathan N, Priya K, Vijaykanth N, Rameshkumar MR, Balakrishnan S. Tumor necrosis factor-alpha level in sera of south indian patients withrheumatoid arthritis: correlation with anticyclic citrullinated peptide antibody level. Asian J Pharm Clin Res 2017;10:118-20.
4. Deepu K, Thomas B, Harindran J. Design, synthesis and evaluation of specific TNF-Î± inhibitory novel dithioic acid derivative from natural acids as anti-inflammatory agents. Int J Pharm Chem 2016;242-9.
5. Rajan T. In silico analysis of compounds characterized from Pseudarthria viscida root with TNF-Î±. J Appl Pharm Sci 2012;2:125â€“8.
6. Halim SA, Jawad M. Attempt to explore the binding mechanism of IL-1Î² inhibitors via molecular docking studies. J Med Chem 2015;5:452â€“7.
7. Hopade A, Ayyad F, Ore Y. Molecular docking studies of phytocompounds from the phyllanthus species as potential chronic pain modulators. Sci Pharm 2014;83:243-67.
8. Sripathy R, Anjana D, Somashekara N, Krishnaraju A, Krishanu S, Murali M, et al. In silico, in vitro and in vivo assessment of safety and anti-inflammatory activity of curcumin. Am J Infect Dis 2012;8:26â€“33.
9. Mallesha H, Dhananjaya K, Ravikumar KR. Molecular docking studies of curcumin and its analogs as inhibitors of arachidonate 5-lipoxygenase for asthma. Int J Comput Bioinfo In silico Model 2015;4:616â€“22.
10. Ikawati Z, Yuniarti N, Margono SA. Acute toxicity and suppressive effects of a curcumin analogue gamavuton-0 (GVT-0-0) on CFA-induced arthritis in rats. J Appl Pharm Sci 2014;4:19â€“23.
11. Yuniarti N, Nugroho PA, Asyhar A, Ikawati Z, Istyastono EP. In vitro and in silico studies on curcumin and its analogues as dual inhibitors for cyclooxygenase-1. ITB J Sci 2012;44:51â€“66.
12. Kumar SS, Anjali T. In silico design and molecular docking studies of some 1, 2-benzisoxazole derivatives for their analgesic and anti inflammatory activity. Int J Curr Pharm Res 2017;9:133-6.
13. Anonymous. Available from: http://www.rcsb.org/pdb/2011. [Last accessed on 08 Sep 2016]
14. Jayaram B. Available from: http://www.scfbio-iitd.res.in/ software/ drugdesign/ lipinski.jsp#anchortag/2009. [Last accessed on 08 Sep 2016]
15. Anonymous. Available from: https://pubchem.ncbi.nlm. nih.gov/ compound/2016. [Last accessed on 08 Sep 2016.
16. Anonymous. Available from: http://lmmd.ecust.edu.cn:8000/ 2012. [Last accessed on 08 Sep 2016]
17. Yang S. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discovery Today 2010;15:444â€“50.
18. Kumar A, Bora U. In silico inhibition studies of NF-kB p50 subunit by curcumin and its natural derivatives. Med Chem Res 2012;21:3281â€“7.
19. Shukla A, Sharma P, Prakash O, Singh M, Kalani K, Khan F, et al. QSAR and docking studies on capsazepine derivatives for immunomodulatory and anti-inflammatory activity. PLoS One 2014;9. Doi:10.1371/journal.pone.0100797.
20. Malkeet Singh B, Silakari. Tumor necrosis factor alpha converting enzymeâ€¯: an encouraging target for various inflammatory disorders tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders. Chem Biol Drug Des 2010;75:415-43.
21. Von Maltzan K, Tan W, Pruett SB. Investigation of the role of TNF-a converting enzyme (TACE) in the inhibition of cell surface and soluble TNF-a production by acute ethanol exposure. PLoS One 2012;7;e29890.
22. R. Dhanalakshmi, R. Manavalan., 2015, In silico docking approach for antiatherosclerotic activity of phytoconstituents of Corchorus aestuans and admet prediction, Asian J. Pharm. Clin. Res, 8, Suppl 2, pp. 350â€“353.
23. Walle L, Vande, Lamkanfi M. Inflammasomes: caspase-1-activating platforms with critical roles in host defense. Front Cell Infect Microbiol 2011;2:1â€“6.
24. Awaluddin R, Muhtadi WK, Chabib L, & Ikawati Z,Molecular Docking and ADME-Toxicity Studies of Potential Compounds of Medicinal Plants Grown In Indonesia as An Anti-rheumatoid Arthritis,In International Conference on Chemistry, Chemical Process and Engineering, 2017: (Vol. 20033).