Rational Design of ALLINI Disrupting IN‐LEDGF/p75 Binding: 3D QSAR, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study

ABSTRACT

The allosteric integrase inhibitors (ALLINI) that disrupt the interaction between the IN and the host co‐factor Lens‐Epithelium Growth Factor (LEDGF/p75) has emerged as a compelling strategy to target the IN. To illuminate the rational basis to design novel ALLINIs an integrated computational approach was carried out, including 3D‐QSAR, scaffold hopping, molecular docking, and molecular dynamics (MD) simulation. A statistically robust model was prepared the 28 reported 5,6,7,8‐tetrahydro‐1,6‐naphthyridine derivatives with R ² value of 0.986 for the training set and Q ² value of 0.679 for the external test set. The electrostatic potential and Van der Waals contour maps provided the insights into the important structural features, that provided the baseline of scaffold hopping. The molecular docking study identified 44 compounds with superior docking scores, of which only 4 displayed favorable pharmacokinetic profiles and were selected for further evaluation. The 300 ns of MD simulation was performed to analyze the structural stability of the four compounds using the trajectory analyses like RMSD, RMSF, RoG, SASA, PCA, H‐bond, and cluster analysis. The study provided a computational framework for designing of ALLINIs with enhanced inhibitory activity and identifies C1 and C4 as a promising candidate for further experimental validation.