2026-09-23 · BACE-1 (β-secretase) — fragment-grown cysteine-sulfoxide small-molecule inhibitor, natural-product-derived starting point (alliin) · chemRxiv

Fragment Growing Explored to Improve a Natural Cysteine-Sulfoxide BACE-1 Inhibitor

BACE-1fragment-based drug designfragment growingmolecular dynamicsAlzheimer's diseasenatural product-derived

Alliin, a natural cysteine-sulfoxide that chelates BACE-1's catalytic dyad, has poor pharmacokinetics, limiting its use as a drug lead.
Researchers used a fragment-growing strategy guided by molecular dynamics simulations to build out from this core, aiming to improve affinity and drug-like properties.
The campaign remains an early-stage computational effort, not a validated clinical candidate.

💡 Points

Starting from a food-derived fragment like alliin is seductive — built-in tox clearance, cheap chirality — but BACE-1 is where good binders go to die clinically (verubecestat, lanabecestat, atabecestat all crashed on safety/efficacy despite clean biochemistry). Growing a fragment computationally is the easy 80%; without disclosed SPR/ITC or crystallography backing the MD poses, I'd treat the affinity gains as hypotheses, not results.

Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics ↗