Thermodynamic Locking of Beta-Amyloid Fibrils: Discovery of a Hyper-Affinity Inhibitor (AP2601-Delta) via Physics-Informed AI

We present AP2601-Delta, a novel Blood-Brain Barrier (BBB) penetrating ligand designed via a physics-informed de novo design framework. Unlike conventional symptomatic treatments, AP2601-Delta targets the hydrophobic core of Beta-Amyloid 42 fibrils with atomic precision. In silico validation confirms a hyper-affinity binding mode (ΔG = -24.74 kcal/mol), driven by a specific chlorine-methyl warhead interaction that thermodynamically locks the fibril structure. The candidate exhibits optimal CNS drug-likeness (LogP 4.11, TPSA 60.17 Ų, QED 0.775) and demonstrates 86.7% structural novelty compared to standard of care, classifying it as a patentable New Chemical Entity (NCE). These results suggest that AP2601-Delta acts as a structural eraser of neurotoxic aggregates, surpassing the limitations of traditional inhibitors.