Computer-Aided Structure-Based Design of Multitarget Leads for Alzheimer’s Disease

Abstract

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.

8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease

“…In previous aggregation inhibition studies using the same MD protocol we could rank the capability of our compounds to inhibit aggregation by evaluating their aptitude to interrupt the formation of a hairpin turn, a structural motif that has been proposed as the possible template for Aβ aggregation. Figure S3 (see Supporting Information) displays the Aβ peptide intra‐residue contact time in the presence and absence of our candidate ligands.…”

“…The results from the experimental binding assays of BACE‐1, inhibition of electric eel AChE ( ee AChE) and horse serum BChE ( hs BChE), as well as the ThT Aβ aggregation inhibition assay, are shown in Table . They indicate that the target to which these compounds bind the strongest is AChE, very much in support of the results of our calculations.…”

“…The great variety of targets opens the door to a new approach aimed at the discovery of molecules addressing simultaneously multiple targets of AD. This novel paradigm, which deviates radically from the traditional “one target‐one molecule strategy”, has recently received increasing attention . The major hurdle in the search for multitarget leads lays on the substantial functional and structural differences amongst the targets, an issue that hinders drastically this therapeutic strategy.…”

“…Recently, we have proposed an in silico procedure for the design of multitarget leads aimed at amyloid cascade and cholinergic pathways in AD . Its first application led us to the discovery of a family of substituted indoles that inhibited Aβ aggregation, BACE‐1, BChE and AChE by binding both its catalytic anionic site (CAS) and PAS . The initial step of the protocol relies on a database search of compounds that comply with a pharmacophore proposed by us.…”

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

“…During the process of drug design for Alzheimer's disease, the size differences in the binding sites of the molecular targets pose a challenge. To overcome this issue, Dominguez et al . have proposed a computer‐assisted protocol that combines pharmacophore modeling, docking, and MD simulations.…”