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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Research Article

2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations

Author(s): Andrea Cuppoloni, João Vitor Silva*, Timothy James Snape, Samridhi Lal and Jeanine Giarolla*

Volume 23, Issue 12, 2023

Published on: 08 March, 2023

Page: [1081 - 1089] Pages: 9

DOI: 10.2174/1568026623666230207120752

Price: $65


Background: Arylindole derivatives are promising scaffolds in the design of new drugs. These scaffolds exhibit a wide biological activity, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogen receptor modulation.

Objectives: Taking this into account, this paper presents a study to understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM, on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations.

Methods: Applying molecular modelling, especially molecular docking, we assessed the SAR of a series of 2,3-arylindoles derivatives in the COX-2 enzyme.

Results: The results indicated that Gly 526 and Phe 381 residues are relevant for improving inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition since it enables a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring.

Conclusion: Therefore, such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies on new selective COX-2 inhibitors.

Keywords: 2, 3-diarylindoles, COX-2 inhibitors, Molecular docking simulations, SAR, Drug design, Ligand interactions, Anti-inflammatory compounds.

Graphical Abstract
Kumar, S. RITIKA, A brief review of the biological potential of indole derivatives. Future J. Pharmaceut. Sci., 2020, 6(1), 1-19.
Singh, T.P.; Singh, O.M. Recent progress in biological activities of indole and indole alkaloids. Mini Rev. Med. Chem., 2018, 18(1), 9-25.
Horton, Douglas.A.; Bourne, Gregory.T.; Smythe, Mark.L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev., 2003, 103(3), 893-930.
Lal, S.; Snape, J. 2-Arylindoles: a privileged molecular scaffold with potent, broad-ranging pharmacological activity. Curr. Med. Chem., 2012, 19(28), 4828-4837.
Chen, C. COX-2’s new role in inflammation. Nat. Chem. Biol., 2010, 6(6), 401-402.
Dey, A.; Kang, X.; Qiu, J.; Du, Y.; Jiang, J. Anti-inflammatory small molecules to treat seizures and epilepsy: From bench to bedside. Trends Pharmacol. Sci., 2016, 37(6), 463-484.
van der Donk, W.A.; Tsai, A.L.; Kulmack, R.J. The cyclooxygenase reaction mechanism. Biochemistry, 2002, 41, 15451-15458.
Rumzhum, N.N.; Ammit, A.J. Cyclooxygenase 2: its regulation, role and impact in airway inflammation. Clin. Exper. Allergy, 2016, 46(3), 397-410.
Fitzgerald, G.A. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nature reviews. Nat. Rev. Drug Discov., 2003, 2(11), 879-90.
Smith, W.L.; Dewitt, D.L.; Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem., 2000, 69, 145-82.
Morales, D.R.; Lipworth, B.J.; Guthrie, B.; Jackson, C.; Donnan, P.T.; Santiago, V.H. Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX2 inhibitors: Meta-analysis of controlled clinical trials. J. Allergy Clin. Immunol., 2014, 134(1), 40-5.
Hu, W.; Guo, Z.; Chu, F.; Bai, A.; Yi, X.; Cheng, G.; Li, J. Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl-indoles: a new series of selective COX-2 inhibitors. Bioorg. Med. Chem., 2003, 11(7), 1153-60.
Biava, M. Introduction to COX inhibitors. Future Med. Chem., 2018, 10(15), 1737-1740.
Huang, H.C.; Li, J.J. Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure−activity relationships. J. Med. Chem., 1996, 39(1), 253-266.
Walker, M.C.; Kurumbail, R.G.; Kiefer, J.R.; Moreland, K.T.; Koboldt, C.M.; Isakson, P.C.; Seibert, K.; Gierse, J.K. A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors. Biochem. J., 2001, 357(Pt 3), 709-18.
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera - A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-12.
Kurumbail, R.G.; Stevens, A.M.; Gierse, J.K.; McDonald, J.J.; Stegeman, R.A.; Pak, J.Y.; Gildehaus, D.; Miyashiro, J.M.; Penning, T.D.; Seibert, K.; Isakson, P.C.; Stalling, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 1996, 384(6610), 644-8.
Orlando, B.J.; Malkowski, M.G. Crystal structure of rofecoxib bound to human cyclooxygenase-2. Acta Crystallogr. Sec., 2016, 72(10), 772-776.
Soliva, R.; Almansa, C.; Kalko, S.G.; Luque, F.J.; Orozco, M. Theoretical studies on the inhibition mechanism of cyclooxygenase-2. Is there a unique recognition site? J. Med. Chem., 2003, 46(8), 1372-1382.
Desiraju, G.R.; Gopalakrishnan, B.; Jetti, R.K.R.; Nagaraju, A.; Raveendra, D.; Sarma, J.A.R.P.; Sobhia, M.E.; Thilagavathi, R. Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis, comparative molecular similarity indices analysis, and docking studies of some 1,2-diarylimidazole derivatives. J. Med. Chem., 2002, 45(22), 4847-57.
Oniga, S.D.; Pacureanu, L.; Stoica, C.I.; Palage, M.D.; Craciun, A.; Rusu, L.R.; Crisan, E.L.; Araniciu, C. COX inhibition profile and molecular docking studies of some 2-(trimethoxyphenyl)-thiazoles. Molecules, 2017, 22(9), 1507.

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