Computational Investigation of the Interaction of Novel Indene Methylene Analogues with Acetylcholinesterase from Both Dynamic and Thermodynamic Perspectives

Background: Torpedo californica acetylcholinesterase (TcAChE) is an important drug development target for Alzheimer's disease (AD) therapeutics. The current in silico study aims to recognise indene methylene-derived compounds acting against TcAChE to gain insight into the molecular interactions. Objective: The current study focused on identifying novel inhibitors for Torpedo californica acetylcholinesterase (TcAChE) by virtual screening, molecular docking, drug-likeness, molecular simulation, and DFT profile for anti-Alzheimer's activity. Methods: Molecular docking, ADMET screening, molecular simulation, and DFT were performed for drug development having anti-Alzheimer's activity related to Torpedo californica acetylcholinesterase (TcAChE). Results: On the AutoDock Vina algorithms, ligands SD-24 [-12.6, -13.1 kcal/mol], SD-30 [-12.5, -12.6 kcal/mol], SD-42 [-11.8, -12.5kcal/mol] showed promising docking and confirmatory redocking scores compared to Donepezil [-8, -10.9 kcal/mol], followed by ADMET screening. The best three complexes were subjected to molecular dynamics simulations (MDSs) over 30 ns to understand the TcAChE dynamics and behavior in a complex with the ligand. MEP and NBO analysis was performed for the DFT/B3LYP theory and 6-311G [d,p] base set and Gaussian 09 package program. For MDSs, the root means square (RMSD) parameter remained stable for 30 ns at 0.25 nm. The ligand-AChE complex formed 2 to 4 satisfactory intermolecular H bonds, which substantiated the stability of the three compounds in the protein binding cluster as potent binders. The LUMO (owest unoccupied molecular orbital)- HOMO (highest occupied molecular orbital) energy gap of the SD24, SD30, and SD42 compounds was 4.0943, 4.2489, and 4.2489 eV, respectively, and stability was ordered as SD24>SD30=SD42. Conclusion: The outcome of in silico studies suggests that SD24, SD30, and SD42 compounds have promising drug-likeness, simulation, and DFT profiles for anti-Alzheimer's activity. However, in vitro and in vivo studies are required to confirm their biological activities.