Natural Sesquiterpenoids from Laggera pterodonta as bioactive Acetylcholinesterase Inhibitors: Insights from DFT, Molecular Docking, and ADMET Profiling

Topic: Disease mechanisms in lab and animal studies

Alzheimer's disease continues to be one of the major critical neurodegenerative ailments of the modern era, with acetylcholinesterase (AChE) inhibition standing as a foundational therapeutic strategy. Natural products continue to provide a rich, sustainable source of structurally diverse bioactive scaffolds that offer sustainable options in the search for new treatments. In this study, five (05) naturally occurring sesquiterpenoids isolated from a single botanical source, Laggera pterodonta , designated as HM-1 to HM-5 , were investigated as potential AChE-targeting candidates through a unified in silico framework, evaluated against the clinically established drug galantamine. Density functional theory (DFT) at the B3LYP/6-311G (d, p) level elucidated the electronic structures of these compounds, including frontier molecular orbitals, density of states, global reactivity descriptors, molecular electrostatic potential, non-covalent interaction topology, and electron localization, while time-dependent DFT further identified their optical signatures Molecular docking showed that all five natural compounds interacted with the AChE active site with binding affinities closer to galantamine; HM-1 had the highest binding value of all (-8.6 kcal/mol ), inducing stable interactions via hydrogen bonding and π-mediated contacts inside the catalytic cavity of the enzyme. A 300 ns molecular dynamics simulation of the AChE– HM-1 complex further supported its conformational stability, with stable backbone RMSD and radius of gyration, persistent hydrogen-bonding interactions, and localized residue flexibility. MM/GBSA analysis yielded a binding enthalpy of − 14.37 ± 0.38 kcal/mol , with van der Waals interactions providing the major favourable energetic contribution, further supporting the stable association of HM-1 with the AChE active site. Notably, ADMET profiling showed that while galantamine retained a slight edge in intestinal absorption and blood-brain barrier permeability, two of the five natural compounds ( HM-1 and HM-5 ) achieved comparable brain penetration, and all five candidates exhibited a safer toxicity profile relative to the reference drug, especially showing reduced neurotoxic and immunotoxin potential.

Key findings

• Density functional theory (DFT) at the B3LYP/6-311G (d, p) level elucidated the electronic structures of these compounds, including frontier molecular orbitals, density of states, global reactivity descriptors, molecular electrostatic potential, non-covalent interaction topology, and electron localization, while time-dependent DFT further identified their optical signatures Molecular docking showed that all five natural compounds interacted with the AChE active site with binding affinities closer to galantamine; HM-1 had the highest binding value of all (-8.6 kcal/mol ), inducing stable interactions via hydrogen bonding and π-mediated contacts inside the catalytic cavity of the enzyme.
• Notably, ADMET profiling showed that while galantamine retained a slight edge in intestinal absorption and blood-brain barrier permeability, two of the five natural compounds ( HM-1 and HM-5 ) achieved comparable brain penetration, and all five candidates exhibited a safer toxicity profile relative to the reference drug, especially showing reduced neurotoxic and immunotoxin potential.

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Study details

• Evidence strengthLow

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• DOI: 10.21203/rs.3.rs-11218173/v1
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@article{iftikhar2026-5f7606f8,
  author  = {Iftikhar, H. and Ejaz, M. M. and Al-Namshah, K. S. and Khan, S. and Ashraf, S. and Meer, N. and Riaz, M. and Saleem, M.},
  title   = {{Natural Sesquiterpenoids from Laggera pterodonta as bioactive Acetylcholinesterase Inhibitors: Insights from DFT, Molecular Docking, and ADMET Profiling}},
  journal = {Research Square},
  year    = {2026},
  doi     = {10.21203/rs.3.rs-11218173/v1},
  url     = {https://doi.org/10.21203/rs.3.rs-11218173/v1}
}

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