Rational scaffold discovery for HIV-1 reverse transcriptase inhibitors via integrated in silico approaches

Human Immunodeficiency Virus-1 (HIV-1) Reverse Transcriptase (RT) remained an epicentre of therapeutic target, yet the efficacy of current non-nucleoside reverse transcriptase inhibitors (NNRTIs) is compromised by drug-induced liver toxicity. In this study, an integrated in silico approach combining similarity-based virtual screening, molecular docking, molecular dynamics, MM-PBSA, followed by molecular descriptor analysis, was employed to identify NNRTI scaffolds with improved safety and efficacy. The similarity-based virtual screening of ZINC and ChEMBL databases, followed by ADMET filtering, highlighted candidates with reduced predicted hepatotoxicity relative to FDA-approved NNRTIs. Among them, ZINC000066352010 exhibited a highly stable binding orientation within the NNRTI binding pocket, stabilized by hydrogen bonding with Lys101 and conserved hydrophobic contacts with Tyr181, Val179, and Trp229. Molecular Dynamics simulations provided compelling validation of this binding mode, as evidenced by the lowest ligand RMSD of 0.05 nm amongst the short-listed candidates, exhibited a persistent average number of hydrogen bonds of 1.95, and markedly reduced backbone fluctuations of RT relative to the apo-protein. These effects indicate enhanced conformational rigidity and long-term stability of the protein-ligand complex. The MM-PBSA provided quantitative thermodynamic support, with a binding energy of - 47.90 Kcal/mol, demonstrating stronger stabilization compared to the reference inhibitor (i.e., 9PJ). The enhanced affinity was driven predominantly by stable Van-der Waals interactions and minimized desolvation penalties. Frontier Molecular Orbital (FMO) and global reactivity descriptor analyses revealed an optimal HOMO-LUMO gap of 0.156 eV and an electrophilicity index of 0.14 eV, positioning it electronically within the window of FDA-approved NNRTIs, thereby indicating balanced reactivity and optimal electronic stability. Complementary electrostatic potential mapping highlighted well-defined reactive centres corroborative to the biomolecular target. Collectively, these findings positioned ZINC000066352010 as a promising NNRTI candidate with improved predicted safety and electronic stability parallel to an FDA-approved drug.