| RRC ID |
63239
|
| 著者 |
Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, Sivaraman DM, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ.
|
| タイトル |
Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors.
|
| ジャーナル |
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.
|
| 巻・号 |
170
|
| ページ |
415-423
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
NH-12(RCB2108) |
