Investigation of the molecular docking of integrase strand transfer inhibitors using the molecular model of the catalytic core of HIV integrase [PDB ID: 6WC8]

Articles in Press

Document Type : Research Articles

Author

• Roohallah Yousefi

1. Behbahan faculty of medical sciences, Behbahan, Iran. 2. Department of Biochemistry, Faculty of biology of Tarbit Modares University, Tehran, Iran.

10.22067/jcmr.2025.89283.1097

Abstract

Introduction: The HIV integrase enzyme, with its N-terminal (NTD), central (CD), and C-terminal (CTD) domains, plays a critical role in the integration of the HIV virus genome into host DNA and the viral life cycle. It accomplishes this by recognizing and binding viral DNA, maintaining structural integrity, and catalyzing integration into the host genome. The CTD domain contains the catalytic core with the DDE motif, which is essential for cleavage and joining reactions, and interacts with LEDGF/p75 to enhance the specificity and efficiency of integration. Inhibitors that block integrase improve HIV treatment and reduce resistance.

Materials and methods: We utilized molecular docking methods to investigate the catalytic core of HIV integrase and its interactions with inhibitory ligands. The physicochemical properties and pharmacokinetics of the compounds under investigation were calculated using the SwissADME webtool database.

Results: Except for compounds with high molecular weight, the remaining compounds exhibit high gastrointestinal absorption, allowing for easy entry into the bloodstream. However, they often have low dermal absorption, which limits their effectiveness for dermal delivery. Compounds with CID numbers 74071, 24800940, and 133081875 demonstrate high dermal absorption. The compound with CID number 91899501 is the only exception, as the other compounds studied bind to a specific site composed of several amino acids. These amino acids, including Gln62, Leu63, Asp64, Val77, His114, Thr115, Asp116, Gly140, Ile141, and Glu152, are crucial for the effective binding of compounds to the enzyme.

Discussion: Understanding the binding sites of integrase strand transfer inhibitors (INSTIs) is crucial for assessing the efficacy of antiretroviral therapy against HIV. The active site of integrase contains the key amino acids D64, D116, and E152, which are targeted by most of the INSTIs studied.

Conclusion: Our study aims to enhance the effectiveness of INSTIs and prevent the development of resistant viruses.

Keywords

• HIV integrase
• Catalytic Core
• INSTIs