Molecular modelling studies of substituted indole derivatives as novel influenza a virus inhibitors

The emergence of drug-resistant strains motivate researchers to find new innovative anti-IAV candidates with a different mode of action. In this work, molecular modelling strategies, such as 2D-QSAR, 3D-QSAR, molecular docking, molecular dynamics, FMOs, and ADMET were applied to some substituted indoles as IAV inhibitors. The best-developed 2D-QSAR models, MLR (Q(2) = 0.7634, R-train(2) = 0.8666) and ANN[4-3-1] (Q(2) = 0.8699, R-train(2) = 0.8705) revealed good statistical validation for the inhibitory response predictions. The 3D-QSAR models, CoMFA (Q(2) = 0.504, R-train(2) = 0.805) and CoMSIA/SEDHA (Q(2) = 0.619, R-train(2) = 0.813) are selected as the best 3D models following the global thresholds. In addition, the contour maps generated from the CoMFA and CoMSIA models illustrate the relationship between the molecular fields and the inhibitory effects of the studied molecules. The results of the studies led to the design of five new molecules (24a-e) with enhanced anti-IAV activities and binding potentials using the most active molecule (24) as the template scaffold. The conformational stability of the best-designed molecules with the NA protein showed hydrophobic and H-bonds with the key residues from the molecular dynamics simulations of 100 ns. Furthermore, the global reactivity indices from the DFT calculations portrayed the relevance of 24c in view of its smaller band gap as also justified by our QSAR and molecular simulation studies.