Reference - Detail
| RRC ID | 63239 |
|---|---|
| Author | Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, Sivaraman DM, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ. |
| Title | Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. |
| Journal | Int J Biol Macromol |
| 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 (IC50 = 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. |
| Volume | 170 |
| Pages | 415-423 |
| Published | 2021-2-15 |
| DOI | 10.1016/j.ijbiomac.2020.12.118 |
| PII | S0141-8130(20)35291-0 |
| PMID | 33373636 |
| MeSH | Alzheimer Disease / drug therapy Aminoacyltransferases / antagonists & inhibitors* Amyloid beta-Peptides / metabolism Brain / drug effects Brain / metabolism Cell Line, Tumor Humans Molecular Docking Simulation Piperidines / pharmacology* Pyrrolidonecarboxylic Acid / metabolism |
| IF | 5.162 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 5 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | NH-12(RCB2108) |