Hamadan University of Medical Sciences Avicenna Journal of Pharmaceutical Research 2717-1884 4 2 2023 12 29 Molecular Docking using MK-2048 and its Structural Analogs Against the HIV-1 Integrase Catalytic Core (PDB ID: 6NUJ) 62 73 10.34172/ajpr.1129 EN Roohallah Yousefi https://orcid.org/0000-0002-1547-6752 Journal Article 10.34172/ajpr.1129 2023 06 08 2023 07 30 Background: This study investigated the molecular docking of MK-2048, a second-generation integrase inhibitor, and compound CID 76212788 against the HIV-1 integrase catalytic core (PDB ID: 6NUJ). The main objective of the study was to comprehend the structural basis of integrase inhibition and pinpoint potential new antiviral agents. Methods: The model of the HIV-1 integrase catalytic core was retrieved from the RCSB PDB database, and the ligands were prepared using Molegro Virtual Docker. The SwissADME tool was utilized to forecast physicochemical properties and pharmacokinetics, while molecular docking was executed using Molegro Virtual Docker. Results: Compound CID 76212788 displayed the strongest binding affinity, establishing hydrogen bonds with essential amino acids of the HIV-1 integrase catalytic core model. These interactions are crucial for designing potent selective inhibitors. The study also emphasized the importance of specific amino acid residues in drug resistance and natural variations among HIV-1 subtypes. All compounds exhibited high gastrointestinal absorption but were unlikely to penetrate the blood-brain barrier. Compound CID 136340365 was identified as a CYP2C19 inhibitor, while CID 54698642, 56841816, 76419031, 68116543, and 136340365 inhibited CYP2C9. Additionally, CID 136340365 and others inhibited CYP2D6. All compounds had low human skin permeability coefficients, suggesting limited dermal absorption. Conclusion: The obtained data underscore the intricacy of HIV genetic diversity and the necessity of developing effective broad-spectrum integrase inhibitors. Further in vitro and in vivo studies are necessary to validate these findings and enhance the compounds for clinical use in the treatment and prevention of HIV infection.