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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
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