Active site binding modes of curcumin in HIV-1 protease and integrase

• Published in: Bioorganic & medicinal chemistry letters 2005-07, Vol.15 (14), p.3364-3368
• Main Authors: Vajragupta, Opa, Boonchoong, Preecha, Morris, Garrett M., Olson, Arthur J.
• Format: Article
• Language: English
• Subjects: 5-CITEP; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites - drug effects; Biological and medical sciences; Computational Biology; Computer Simulation; Crystallization; Crystallography, X-Ray; Curcumin; Curcumin - chemistry; Curcumin - pharmacology; Docking; Drug Design; HIV integrase; HIV Integrase - chemistry; HIV Integrase - drug effects; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV protease; HIV Protease - chemistry; HIV Protease - drug effects; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Protein Conformation; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.05.032

Computational docking of curcumin with HIV-1 integrase (IN) and protease (PR) is reported. Structure models for the interaction of curcumin with HIV-1 integrase (IN) and protease (PR) were investigated using computational docking. Curcumin was found to bind preferentially in similar ways to the active sites of both IN and PR. For IN, the binding site is formed by residues Asp64, His67, Thr66, Glu92, Thr93, Asp116, Ser119, Asn120, and Lys159. Docked curcumin contacts the catalytic residues adjacent to Asp116 and Asp64, and near the divalent metal (Mg 2+). In the PR docking, the curcumin structure fitted well to the active site, interacting with residues Asp25, Asp29, Asp30, Gly27′, Asp29′, and Asp30′. The results suggest that o-hydroxyl and/or keto–enol structures are important for both IN and PR inhibitory actions. The symmetrical structure of curcumin seems to play an important role for binding to the PR protein, whereas the keto–enol and only one side of the terminal o-hydroxyl showed tight binding to the IN active site.