Molecular Docking Evaluation of Curcumin, Ursolic Acid, Quercetin, Berberine, and Andrographolide Against HIV-1 Reverse Transcriptase and Protease

This molecular docking study successfully evaluated the binding potential of five phytochemicals—curcumin, ursolic acid, quercetin, berberine, and andrographolide—against HIV-1 reverse transcriptase and protease. Curcumin emerged as the best overall candidate for reverse transcriptase inhibition with the highest binding affinity (-11.5 kcal/mol), forming four hydrogen bonds with Lys101, Tyr181, Tyr188, and Asp185. Its favorable ADMET profile (high absorption, positive BBB permeability, low toxicity) and dual "High" rating position curcumin as the top lead compound for further development. Ursolic acid demonstrated the most potent protease inhibition (-10.8 kcal/mol) through extensive hydrophobic contacts with catalytic Asp25, Asp29, and flap region residues Ile50 and Ile84. The rigid pentacyclic structure provides entropic advantages for stable complex formation. Quercetin showed balanced multi-target activity against both RT (-9.5 kcal/mol) and protease (-9.5 kcal/mol), with a binding affinity difference of only 0.1 kcal/mol. The planar flavonoid core facilitated π-π stacking and hydrogen bonding with both enzymes, suggesting potential for broad-spectrum anti-HIV activity. Berberine exhibited moderate RT binding (-9.3 kcal/mol) with unique electrostatic interactions through its quaternary nitrogen. Its high absorption and positive BBB permeability make it a candidate for addressing HIV-associated neurocognitive disorders. Andrographolide showed the lowest binding affinity (-8.5 kcal/mol) among tested compounds but targets gp120, representing a distinct entry inhibition mechanism that may complement intracellular inhibitors in combination therapy. All five compounds exhibited low predicted toxicity and favorable drug-likeness properties, supporting their safety for further investigation. These findings provide a strong computational foundation for in vitro and in vivo validation of these phytochemicals as potential anti-HIV therapeutic agents.

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