Putting the Puzzle Together To Get the Whole Picture: Molecular Basis of the Affinity of Two Steroid Derivatives to Acetylcholinesterase

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has no cure because its etiology still unknown, and main treatment the administration of acetylcholinesterase (AChE) inhibitors. The study mechanism action this family compounds critical for design new more potent specific In work, we molecular basis an uncompetitive inhibitor (compound 1, 2β, 3α-dihydroxy-5α-cholestan-6-one disulfate), which have proved to be peripheral anionic site (PAS)-binding AChE inhibitor. pipeline designed in work key development other PAS inhibitors not only inhibit esterase enzyme but could also modulate non-cholinergic functions linked process amylogenesis. Our studies showed 1 inhibits simply by blocking gate allosteric mechanism. A detailed careful analysis ligand binding position protein dynamics, particularly regarding their secondary gates active site, was necessary conclude this. same executed with inactive analogue 2, 3α-dihydroxy-5α-cholestan-6-one). first computational results differences affinity between both steroids, making further necessary. This highlights variables considered develops refined methodology, successful dual-action drugs AD, inhibitors, attractive strategy combat AD.