Integrated computational-based design of putative dual TrkA/TrkB agonists for Alzheimer’s disease: pharmacophore modelling, docking, MM/GBSA, DFT and dynamics studies

Background: The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases. Aim: This study aims to develop novel dual TrkA/TrkB receptor agonists for the treatment of AD by enhancing neurotrophin signalling, reducing cholinergic denervation, and mitigating amyloid-β-induced neurotoxicity. Methods: drug discovery pipeline was employed, involving homology and pharmacophore modelling of amitriptyline, virtual screening of ChEMBL compounds, molecular docking, ADMET, MM/GBSA analysis, DFT calculations and molecular dynamics (MD) simulations for 100 and 300 ns to assess ligand stability and binding behaviour of the ligand-protein complexes. Results: Six novel optimised quinoline analogues (OP-1 to OP-6) were identified as computationally predicted dual TrkA/TrkB agonists by molecular docking (-8.90 to -5.07 kcal/mol), MM/GBSA (-40.47 to -30.71 kcal/mol), ADMET and DFT analysis. Furthermore, OP-1, OP-2, and OP-3 exhibit stable binding interactions over 300 ns of MD simulations. The optimised compounds demonstrated favorable computational binding profiles, predicted pharmacokinetic properties, and stable receptor-ligand interactions, identifying them as promising candidates for further experimental validation as potential dual TrkA/TrkB modulators in Alzheimer's disease.