Mechanistic multiscale modeling identifies putative natural tri-target candidates of MAO-B, LRRK2 and A₂A for Parkinson's disease.
Mechanistic multiscale modeling identifies putative natural tri-target candidates of MAO-B, LRRK2 and A₂A for Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Oujda, MA · Author affiliation
Faculty of sciences, department of Chemistry, Laboratory of Applied and Environmental Chemistry (LCAE), Mohammed Premier University, Oujda, Morocco. oussama.khibech.d24@ump.ac.ma.Location evidence
Lille, FR · Author affiliation
Department of Pharmacy, UFR3S, TBC Laboratories, University of Lille, 3 rue du Professeur Laguesse, BP 83, Lille Cedex, 59006, France.Location evidence
Nablus, PS · Author affiliation
Department of Chemistry, An-Najah National University, P.O. Box 7, Nablus, Palestine. sjodeh@najah.edu.Location evidence
Hudson, US · Author affiliation
Division of Pulmonary, Critical Care and Sleep Medicine, Detroit Medical Centre, Wayne State University School of Medicine, 3990 John R-3 Hudson, Detroit, MI, 48201, USA.Location evidence
Detroit, US · Author affiliation
Division of Pulmonary, Critical Care and Sleep Medicine, Detroit Medical Centre, Wayne State University School of Medicine, 3990 John R-3 Hudson, Detroit, MI, 48201, USA.Location evidence
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Original abstract
Parkinson's disease (PD) is a rapidly growing neurodegenerative disorder for which current dopaminergic and device-based therapies remain purely symptomatic and fail to modify disease progression. Addressing the multifactorial biology of PD under stringent blood-brain barrier constraints requires CNS-penetrant small molecules that can simultaneously engage several validated targets. Here, we combined ADMET-AI profiling, structure-based docking, 100 ns molecular dynamics, MM/GBSA ensemble free energies, and principal component analysis to evaluate falcarinol, 20-hydroxyecdysone, and arnicolide D as putative tri-target candidates of MAO-B, LRRK2 and the A₂A receptor. Falcarinol and arnicolide D occupy a CNS drug-like ADMET space with high predicted BBB penetration and acceptable safety, and show stable, hydrophobically driven binding across all three proteins. In contrast, 20-hydroxyecdysone achieves the most favorable MM/GBSA binding free energies in MAO-B and A₂A (ΔGbind down to -53.4 and - 56.6 kcal·mol⁻¹, respectively) through persistent multi-point hydrogen bonding. Still, it lies outside the optimal CNS physicochemical window. Integrating these orthogonal readouts, we propose an ADMET-constrained multi-target pharmacophore framework for simultaneous MAO-B/LRRK2/A₂A modulation and nominate falcarinol- and arnicolide D-based chemotypes, alongside polarity-masked 20-hydroxyecdysone analogues, as prioritized starting points for experimental validation and next-generation multi-target-directed ligands in Parkinson's disease.