4-Oxoquinoline Ribonucleosides as HIV-1 Reverse Transcriptase Inhibitors: A combination of DFT, QSAR Study, Docking Simulation, and ADMET Prediction

Despite significant advancements in diagnosis and treatment, the human immunodeficiency virus (HIV-1) remains a severe and life-threatening challenge. Given the essential role of the viral enzyme reverse transcriptase (RT) in HIV replication, RT inhibitors are a promising class of therapeutic agents. In this study, density functional theory (DFT) calculations were performed to evaluate the reactivity and chemical properties of 21 4-oxoquinoline ribonucleosides. Two quantitative structure-activity relationship (QSAR) models for these antiviral compounds were generated using multiple linear regression (MLR) and CoMFA chemometric methods. The models demonstrated statistically significant internal and external validation results, with values of 0.92 and 0.999, values of 0.8 and 0.535, values of 0.65 and 0.715, values of 0.67 and 0.604, and values of 0.01 and -0.221, respectively. The predictive CoMFA model was used to identify key structural areas where modifications could improve the antiviral activity of 4-oxoquinoline ribonucleoside derivatives. Additionally, molecular docking (MD) of the most active antiviral molecule with the HIV-1 RT binding site was conducted to clarify its binding mode and pinpoint critical interacting residues within the active site. The MD results corroborated the findings from the 3D-QSAR model. Furthermore, an ADMET study was performed on the antiviral compounds to assess their safety and efficacy profiles. These findings highlight the potential of the investigated agents as promising HIV RT inhibitors, warranting further in-depth studies.