Title : Structure based virtual screening and molecular docking of ALZ 801 analogues targeting A? Aggregation for Alzheimer’s disease therapy
Abstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which soluble β?amyloid (Aβ) oligomers are key upstream drivers of synaptic dysfunction and cognitive decline. ALZ?801 (valiltramiprosate) is an oral valine?Conjugated prodrug of tramiprosate that inhibits Aβ42 oligomer formation by a multi?ligand “enveloping” interaction with Aβ monomers, stabilizing them and preventing misfolding and aggregation.
In this context, the present work employs structure?based virtual screening and molecular docking to design and prioritize ALZ?801–inspired small molecules targeting Aβ42, with the goal of enhancing anti?oligomer potency and optimizing drug?like properties. Candidate ligands are evaluated for binding to key residues (e.g., Lys16, Lys28, Asp23) that mediate tramiprosate’s enveloping mechanism, ranked by predicted affinity and interaction patterns, and filtered using in silico ADMET profiling. By integrating clinically validated mechanistic insights from ALZ-801 with rational in-silico drug design strategies, this work provides a systematic framework for the development of next-generation oral Aβ anti-oligomer agents. The findings highlight the role of computational approaches in accelerating early-stage discovery and advancing disease-modifying therapeutic options for early intervention in Alzheimer’s disease. This computational pipeline not only refines ALZ-801’s mechanism but also paves the way for potent, orally bioavailable therapeutics to halt oligomer-driven pathology.
