J Chem Inf Model - Computer-aided structure-based design of multitarget leads for Alzheimer's disease.

Tópicos

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Resumo

Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.

Resumo Limpo

alzheim diseas neurodegen patholog unmet clinic need high desir approach syndrom find singl lead bind select biomolecul particip amyloid cascad accept rout alzheim diseas genesi order circumv challeng pose sizabl differ bind site molecular target propos computerassist protocol base pharmacophor set requir interact target allow autom screen candid use combin dock molecular dynam protocol order discard nonbind optim best candid provid rational potenti inhibitor provid proof concept proceed screen literatur databas task allow us identifi set carbazolecontain compound initi show affin cholinerg target experiment assay two cycl design base protocol led new set analogu synthes assay assay result reveal design inhibitor improv affin bace order magnitud also display amyloid aggreg inhibit affin ach buch result led us group multitarget amyloid cascad inhibitor also posit effect cholinerg level

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