Molecular modelling studies on novel pleconaril derivatives as antienteroviral agents

Anti-enteroviral denotes agents intended to prevent or treat infections caused by enteroviruses a broad class of viruses including poliovirus, coxsackieviruses and rhinovirus that are responsible for diseases ranging from mild respiratory illnesses to severe clinical conditions. At present, there are no approved virus-specific therapies for enteroviral infections. The present study emphasizes a molecular modeling investigation of Pleconaril derivatives to identify promising lead compounds for the treatment of enteroviral infections. The ligand library that was responsible for reporting the anti-enteroviral activities was derived from the literature that contained twenty four novel pleconaril derivatives. To design future analogs of the novel pleconaril derivatives, research was done to develop the Atom-based and Field-based-3D QSAR (Quantitative structure-activity relationship models) models. PHASE was utilized for generating a common pharmacophore and conducting 3D-QSAR studies. The protein target (PDB ID: 4WM7) was chosen, and docking was performed to identify optimal binding modes between the target and ligands. EV-D68’s crystal structure and its complex with pleconaril (PDB ID: 4WM7) had 2.32 Å resolution. The free energy was calculated using PRIME-Molecular Mechanics with Generalized Born and Surface Area Solvation (MM/GBSA). Molecular properties and ADME parameters were assessed with the QikProp utility and SwissADME. In the docking study, molecule 12b had a docking score of -12.210 kcal/mol and was most closely aligned with 4WM7. Compared to Pleconaril (-11.466 kcal/mol), a natural ligand, it was more effectively docked. All compounds, with the exception of a small number, had values that fell within a reasonable range. The rule of five values fell within the acceptable range. We chose the top-ranked six-point hypothesis, AHHRRR_1. All active compounds were correlated with the developed best-ranking hypothesis by aligning them on the chosen pharmacophore AHHRRR_1. In conclusion, 3D-QSAR models, and free energy were calculated, ADME parameters were assessed, and a comparative docking study of the pleconaril derivatives against the enterovirus target.