Multiscale Computational Prioritization of Chromone-Based Acetylcholinesterase Ligands
5 affiliations
- 1Laboratory of Materials Chemistry and Applications (LCMA), Department of Chemistry, Faculty of Sciences, Mohammed Premier University, BP 717, Oujda 60000, Morocco
- 2Laboratory of Physical Chemistry of Materials, Natural Substances and Environment, Chemistry Department, Faculty of Sciences and Techniques of Tangier, Tangier 90090, Morocco
- 3Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Mghila, P.O. Box 523, Beni Mellal 23000, Morocco
- 4Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
- 5BioSTM—UR 7537 Biostatistics, Processing and Modelling of Biological Data, Université Paris Cité, 75006 Paris, France
Abstract
Identifying acetylcholinesterase (AChE) ligands for Alzheimer’s disease research requires integrating molecular recognition with pharmacokinetic and safety considerations. Here, four designed chromone derivatives (M1–M4) were investigated to determine how conformational sampling and complementary molecular descriptors refine docking-based prioritization. Donepezil redocking in human AChE and cross-docking into Torpedo californica AChE recovered the crystallographic and transferred reference orientations, respectively, with RMSDs of 0.942 and 1.074 Å. Molecular docking was integrated with 800 ns molecular dynamics, MM/PBSA, electronic-structure calculations, and pharmacokinetic/toxicity predictions. M4 achieved the most favorable chromone docking score (−9.6 kcal mol−1), whereas M3 yielded the most favorable chromone MM/PBSA estimate within the 775–800 ns window (−23.90 ± 2.31 kcal mol−1). Donepezil retained a more favorable MM/PBSA estimate (−41.00 ± 2.75 kcal mol−1). M4 exhibited the highest electronic hardness, while predicted toxicity profiles revealed distinct liabilities across the series. The divergence between docking and sampled energetics highlights the value of integrating complementary criteria when selecting compounds for experimental evaluation. These protocol-dependent findings prioritize M3 and M4 as complementary computational candidates requiring experimental confirmation of AChE inhibition, selectivity, and safety.
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BibTeX
@article{khibech2026multiscale,
title = {{Multiscale Computational Prioritization of Chromone-Based Acetylcholinesterase Ligands}},
author = {Oussama Khibech and Bahia Abdelfattah and Mohamed Bouhrim and Moneerah J. Alqahtani and Jawaher H. Alqahtani and Joe Miantezila Basilua and Aziz Boulouiz and Rachid Touzani},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209153},
url = {https://www.mdpi.com/1422-0067/27/20/9153},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Multiscale Computational Prioritization of Chromone-Based Acetylcholinesterase Ligands
AU - Oussama Khibech
AU - Bahia Abdelfattah
AU - Mohamed Bouhrim
AU - Moneerah J. Alqahtani
AU - Jawaher H. Alqahtani
AU - Joe Miantezila Basilua
AU - Aziz Boulouiz
AU - Rachid Touzani
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209153
UR - https://www.mdpi.com/1422-0067/27/20/9153
AB - Identifying acetylcholinesterase (AChE) ligands for Alzheimer’s disease research requires integrating molecular recognition with pharmacokinetic and safety considerations. Here, four designed chromone derivatives (M1–M4) were investigated to determine how conformational sampling and complementary molecular descriptors refine docking-based prioritization. Donepezil redocking in human AChE and cross-docking into Torpedo californica AChE recovered the crystallographic and transferred reference orientations, respectively, with RMSDs of 0.942 and 1.074 Å. Molecular docking was integrated with 800 ns molecular dynamics, MM/PBSA, electronic-structure calculations, and pharmacokinetic/toxicity predictions. M4 achieved the most favorable chromone docking score (−9.6 kcal mol−1), whereas M3 yielded the most favorable chromone MM/PBSA estimate within the 775–800 ns window (−23.90 ± 2.31 kcal mol−1). Donepezil retained a more favorable MM/PBSA estimate (−41.00 ± 2.75 kcal mol−1). M4 exhibited the highest electronic hardness, while predicted toxicity profiles revealed distinct liabilities across the series. The divergence between docking and sampled energetics highlights the value of integrating complementary criteria when selecting compounds for experimental evaluation. These protocol-dependent findings prioritize M3 and M4 as complementary computational candidates requiring experimental confirmation of AChE inhibition, selectivity, and safety.
SN - 1422-0067
ER -