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Background <p>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.</p> Methods <p>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.</p> Results <p>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&#xa0;kcal/mol, superior to the reference inhibitor rivastigmine (− 6.4&#xa0;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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年4月13日

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  • Satyavani Meesala,
  • Swathi Nageswara,
  • Rajkiran Kolakota,
  • Muni Kumar Dokka,
  • Mumpi Giri,
  • Priyadarsini Bada,
  • Vidya Sagar Jerra

摘要

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.