Molecular Docking using MK-۲۰۴۸ and its Structural Analogs Against the HIV-۱ Integrase Catalytic Core (PDB ID: ۶NUJ)

Background: This study investigated the molecular docking of MK-۲۰۴۸, a second-generation integrase inhibitor, and compound CID ۷۶۲۱۲۷۸۸ against the HIV-۱ integrase catalytic core (PDB ID: ۶NUJ). 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-۱ 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 ۷۶۲۱۲۷۸۸ displayed the strongest binding affinity, establishing hydrogen bonds with essential amino acids of the HIV-۱ 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-۱ subtypes. All compounds exhibited high gastrointestinal absorption but were unlikely to penetrate the blood-brain barrier. Compound CID ۱۳۶۳۴۰۳۶۵ was identified as a CYP۲C۱۹ inhibitor, while CID ۵۴۶۹۸۶۴۲, ۵۶۸۴۱۸۱۶, ۷۶۴۱۹۰۳۱, ۶۸۱۱۶۵۴۳, and ۱۳۶۳۴۰۳۶۵ inhibited CYP۲C۹. Additionally, CID ۱۳۶۳۴۰۳۶۵ and others inhibited CYP۲D۶. 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.