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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Arylindole derivatives are versatile scaffolds with diverse biological activities.
• These compounds show potential for inhibiting cyclooxygenase-2 (COX-2), a key target in inflammation and cancer.
• Previous research highlights their utility in drug design.

Purpose of the Study:

• To investigate the inhibitory action of 2,3-diarylindoles on the COX-2 enzyme.
• To elucidate the structure-activity relationship (SAR) of these compounds using molecular docking.
• To identify key molecular interactions responsible for COX-2 inhibition.

Main Methods:

• Utilized molecular modeling and molecular docking simulations.
• Assessed the SAR of a series of 2,3-diarylindole derivatives against COX-2.
• Analyzed interactions between compounds and COX-2 active site residues.

Main Results:

• Identified Gly 526 and Phe 381 residues as crucial for enhanced inhibition of para-substituted 3-phenyl compounds.
• Demonstrated the importance of Arg 120 for COX-2 inhibition via π-cation interaction with the potent A5 compound (IC50 = 0.006 nM).
• Observed active site flexibility in COX-2 accommodating 5-substituted indole ring compounds.

Conclusions:

• The identified structural features are valuable for designing new selective COX-2 inhibitors.
• Findings can guide future Structure-Based Drug Design (SBDD) and Ligand-Based Drug Design (LBDD) studies.
• This research provides a foundation for developing targeted anti-inflammatory and anti-cancer agents.