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Alzheimer's disease drug candidates stabilize A-? protein native structure by interacting with the hydrophobic core.

ABSTRACT: Deposition of amyloid fibrils, consisting primarily of A?(40) and A?(42) peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of A? peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the A?(42) monomer at its ?-helical conformation and a pentamer fibril fragment of A?(42) peptide with or without LRL and fluorene series compounds to investigate the mechanism of inhibition. The results show that the active drug candidates, LRL22 (EC(50) = 0.734 ?M) and K162 (EC(50) = 0.080 ?M), stabilize hydrophobic core I of A?(42) peptide (residues 17-21) to its ?-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC(50) > 10 ?M) and K182 (EC(50) > 5 ?M), have little to no similar effect. This explains the different behavior of the drug candidates in experiments. Of more importance, this phenomenon indicates that hydrophobic core I of the A?(42) peptide plays a major mechanistic role in the formation of amyloid fibrils, and paves the way for the development of new drugs against AD.

SUBMITTER: Li J

PROVIDER: S-EPMC3037571 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Alzheimer's disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core.

Li Jie J Liu Ruiwu R Lam Kit S KS Jin Lee-Way LW Duan Yong Y

Biophysical journal 20110201 4

Deposition of amyloid fibrils, consisting primarily of Aβ(40) and Aβ(42) peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of Aβ peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the Aβ(42) monomer at its α-helical conformation and a pentamer fibril fragment of Aβ(42) peptide with or without ...[more]

PMID: 21320453

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Project description:BackgroundDespite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies.MethodsHere, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.ResultsWe identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.ConclusionsThis study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients.

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Alzheimer's disease drug candidates stabilize A-? protein native structure by interacting with the hydrophobic core.

Publications

Alzheimer's disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core.

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