Targeting the Alzheimer's-Linked Protease SPPL2a: A Multistage Virtual Screening and Molecular Dynamics Framework for Identifying Selective Inhibitors over Presenilin-1

<p dir="ltr">Targeting the intramembrane aspartyl protease SPPL2a (Signal peptide-peptidase like 2a) offers a compelling strategy in Alzheimer’s disease to clear pathogenic substrates such as TMEM106B without triggering the fatal Notch toxicities of γ-secretase/Presenilin-1 (PS1) inhibition, however, therapeutic development has been hindered by its active site conservation with PS1. To address this, we conducted a multistage virtual screening campaign across 244,574 molecules from three chemical repositories – ZINC15, Enamine REAL, and Aurigene Discovery, prioritizing candidates through progressive docking, MM-GBSA rescoring, and 500 ns all-atom membrane molecular dynamics in a POPC bilayer, unveiling ZINC Top 1 as a potent lead candidate.</p>