In silico pharmacophore-guided modeling of marine-derived γ-secretase modulators for amyloid-beta reduction in Alzheimer's disease

Alzheimer's disease is primarily caused by the accumulation of amyloid-beta (Aβ) proteins, with γ-secretase playing a key role in the formation of Aβ (1-42). This study aimed to identify novel γ-secretase modulators from a wide range of marine organisms that selectively lower Aβ production. Using BMS 299897 and ELN 318463 as reference drugs, we developed a Shared Feature Pharmacophore (SFP) map featuring one hydrogen bond donor, three hydrogen bond acceptors, four hydrophobic regions, two aromatic bonds, and two halogen bond donors. Screening a library of 47,451 marine-derived compounds through this map identified six promising hits. Synthetic γ-secretase modulators were designed using fragment-based drug design by integrating bioactive fragments from these hits with the essential 4-chlorobenzenesulfonamide ring of the reference drugs. Molecular docking and pharmacokinetic analyses highlighted three compounds, Molecule 6 (−10.6 kcal/mol), Molecule 24 (−9.7 kcal/mol), and Molecule 28 (−9.6 kcal/mol), all of which exhibited stronger binding affinities than the control drug BMS 299897 (−8.9 kcal/mol) and showed favorable blood-brain barrier permeability. Additionally, 100 ns molecular dynamics simulations demonstrated stable conformational dynamics and robust interactions for Molecule 24. Further, toxicity profiling of the designed modulators, including Molecule 24, was conducted using the OECD QSAR Toolbox v4.7.1, revealing favorable bioavailability and reduced bioaccumulation. To ensure practical feasibility, a computational sequence-to-sequence retrosynthesis route for Molecule 24 was developed for efficient deconstruction into accessible intermediates and precursors. These overall findings are promising, but they need to be validated through in vitro and in vivo studies to confirm their effectiveness and safety as potential Alzheimer's treatments.