Pharmacophore-Guided Computational 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 marine resources that selectively lower Aβ production. Using BMS 299897 and ELN 318463 as reference drugs, we developed a Shared Feature Pharmacophore (SFP) map featuring 1 hydrogen bond donor, 3 hydrogen bond acceptors, 4 hydrophobic regions, 2 aromatic bonds, and 2 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, Molecule 24, and Molecule 28) with stronger binding affinities than BMS 299897 and favorable blood-brain barrier permeability. Additionally, 100 ns molecular dynamics simulations demonstrated stable conformational dynamics and robust interactions for Molecule 24. While these findings are promising, further experimental validation is necessary to confirm the effectiveness and safety of these compounds as potential Alzheimer’s treatments.