Computational Screening of Columbianadin-Derived Furanocoumarins as Multitarget Neurotherapeutics Against MAO-B, AChE, and BACE1 For Alzheimer's Disease

Abstract

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by multiple pathological pathways, including monoamine oxidase activity, cholinergic dysfunction, and amyloid-β peptide accumulation. Developing multi-targeted neurotherapeutics has emerged as a promising approach to address this multifactorial nature of AD. Furanocoumarins, including Columbianadin, possess structurally diverse scaffolds with broad pharmacological properties and may be suitable candidates for multi-target modulation. Objective: This study aimed to computationally screen Columbianadin-derived furanocoumarins against Monoamine Oxidase B (MAO-B), Acetylcholinesterase (AChE), and β-Secretase 1 (BACE1) to identify potential natural product-based multi-target neurotherapeutics for AD. Methods: Columbianadin-derived furanocoumarins were retrieved from the PubChem database and evaluated for CNS-likeness, pharmacokinetic properties and toxicity profiles. The qualified compounds were subjected to consensus molecular docking against MAO-B, AChE and BACE1 using the FRED (OpenEye, Chemgauss4 scoring), , Glide and Prime (MM-GBSA) resoring to prioritize compounds by cross-docking . The top-ranked multi-target compound was further assessed for binding pose stability through molecular dynamics (MD) simulations using DESMOND 2021.4 package and its frontier molecular orbital (FMO) and electronic reactivity properties were characterized by density functional theory (DFT). Results: Molecular docking identified several compounds with favorable binding profiles across MAOB, AChE, and BACE1. Amongst these, PubChem ID 132962208 was consistently prioritized across all three scoring engines . MD simulations confirmed the stability of docked complexes, showing sustained interactions and minimal conformational fluctuations throughout the 200 ns simulation course. DFT analysis further indicated consistent HOMO–LUMO gap and electronic reactivity profile with a stable drug-like scaffold. Conclusion: The computational screening highlights Columbianadin-derived furanocoumarins, particularly compound with PubChem ID 132962208, as promising natural multi-target neurotherapeutic for AD. These computational findings provide a strong foundation for further experimental validation and development as a potential therapeutic regimen for AD.