In silico prediction of octahydro-1H-indole-2-carboxamide derivatives as novel acetylcholinesterase inhibitors: a comprehensive computational study

Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline and memory loss. Acetylcholinesterase (AChE)inhibition remains a crucial therapeutic strategy for AD treatment. This study aimed to identify novel octahydro-1H-indole-2-carboxamide derivatives as potential AChE inhibitors through comprehensive computational approaches. Methods A library of thirty derivatives was designed and subjected to comprehensive in silico screening. The AChE binding pocket was identified using the CASTp server, followed by high-throughput virtual screening (HTVS) in AutoDock. Pharmacokinetic and drug-likeness parameters were predicted using SwissADME, while toxicity profiles were assessed via ProTox. The top-scoring compound (STY9) underwent a 100ns molecular dynamics (MD) simulation to evaluate binding stability and interaction consistency. Results CASTp analysis revealed a well-defined active site pocket suitable for ligand accommodation. Docking results identified STY9 as the most promising candidate, showing a binding affinity of − 9.17 kcal/mol, superior to the reference inhibitor rivastigmine (− 6.4 kcal/mol). SwissADME predictions indicated favourable absorption and BBB permeability, while ProTox analysis suggested low toxicity potential. MD simulations confirmed stable binding of STY9 with minimal structural fluctuations, supporting a robust enzyme–ligand complex. Conclusion This integrated computational approach highlights STY9 as a potent and pharmacokinetically favourable AChE inhibitor scaffold. The findings provide a favourable indication for future experimental validation and the development of structurally optimised analogues for Alzheimer’s disease therapy.