AI Article Synopsis
- Alzheimer's disease (AD) is a serious neurodegenerative condition with limited treatment options, largely due to the toxic variant of amyloid beta (pGlu-Aβ) formed by the overexpression of secretory glutaminyl cyclase (sQC).
- A new study identifies a potential sQC inhibitor, Cpd-41, which shows promise in preventing the toxic effects of pGlu-Aβ, with an inhibitory concentration (IC) of 34 μM.
- Advanced techniques like molecular docking, MD simulations, and X-ray crystallography reveal how Cpd-41 binds to the active site of sQC, suggesting it could lead to the development of stronger sQC inhibitors with manageable toxicity.
Article Abstract
Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC = 34 μM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.
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| http://dx.doi.org/10.1016/j.ijbiomac.2020.12.118 | DOI Listing |
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