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<p>This study aimed to examine 3000 natural as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by using a combining molecular docking, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and&#xa0;pharmacokinetic (ADME) profiling. The initial validation of the docking protocol demonstrated reliability with RMSD values below 2.0&#xa0;Å for galantamine (AChE) and tacrine (BChE). Docking results revealed that twelve natural compounds had higher binding affinities than native ligands, with binding energies ranging from −&#xa0;10.74 to −&#xa0;11.60&#xa0;kcal/mol for AChE and −&#xa0;9.28 to −&#xa0;11.03&#xa0;kcal/mol for BChE. Among them, compounds CID 441663 and 10,621 showed particularly stable binding. Pharmacokinetic and ADMET evaluations reveal that CID 23815268 and CID 10253785 exhibited safer profiles with minimal toxicity and environmental risk, although CID 10253785 showed reduced binding stability in MD simulations. Molecular dynamics simulations confirmed the structural stability of these top candidates, with low RMSD and RMSF values indicating strong and consistent binding within the enzymes’ active sites. MM/GBSA analysis revealed CID 441663 as the most potent AChE inhibitor (− 84.99&#xa0;kcal/mol), while CID 31553 showed the highest binding affinity to BChE (− 69.16&#xa0;kcal/mol). These compounds CID 441663, CID 23815268, CID 10621, and CID 31553 emerged as the most promising multi-target cholinesterase inhibitors, offering strong binding affinities, dual AChE/BChE inhibition, and encouraging pharmacokinetic profiles, positioning them as lead candidates for further development in Alzheimer’s therapy. </p>

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Identification of natural product inhibitors as potential drug candidates for treating Alzheimer's disease: molecular docking, molecular dynamics simulations, MM/GBSA and pharmacokinetics

  • 期刊论文

  • 发表日期：

    2025年6月29日

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  • Ahmed Boufissiou,
  • Mohnad Abdalla,
  • Imededdine Kadi,
  • Hachani Soumaya,
  • Wafa Ali Eltayb,
  • Maaweya E. Awadalla,
  • Alanood Saeed Algarni,
  • Adel Benarfa,
  • Abderrezak Bouchareb,
  • Farouk Benaceur,
  • Fathi Berrabah

摘要

This study aimed to examine 3000 natural as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by using a combining molecular docking, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and pharmacokinetic (ADME) profiling. The initial validation of the docking protocol demonstrated reliability with RMSD values below 2.0 Å for galantamine (AChE) and tacrine (BChE). Docking results revealed that twelve natural compounds had higher binding affinities than native ligands, with binding energies ranging from − 10.74 to − 11.60 kcal/mol for AChE and − 9.28 to − 11.03 kcal/mol for BChE. Among them, compounds CID 441663 and 10,621 showed particularly stable binding. Pharmacokinetic and ADMET evaluations reveal that CID 23815268 and CID 10253785 exhibited safer profiles with minimal toxicity and environmental risk, although CID 10253785 showed reduced binding stability in MD simulations. Molecular dynamics simulations confirmed the structural stability of these top candidates, with low RMSD and RMSF values indicating strong and consistent binding within the enzymes’ active sites. MM/GBSA analysis revealed CID 441663 as the most potent AChE inhibitor (− 84.99 kcal/mol), while CID 31553 showed the highest binding affinity to BChE (− 69.16 kcal/mol). These compounds CID 441663, CID 23815268, CID 10621, and CID 31553 emerged as the most promising multi-target cholinesterase inhibitors, offering strong binding affinities, dual AChE/BChE inhibition, and encouraging pharmacokinetic profiles, positioning them as lead candidates for further development in Alzheimer’s therapy.