8EPO

Co-crystal structure of Chaetomium glucosidase with compound 18

これはPDB形式変換不可エントリーです。

8EPO の概要

• エントリーDOI: 10.2210/pdb8epo/pdb
• 分子名称: Chaetomium alpha glucosidase, GLYCEROL, (3P)-3-(5,6-dihydro-1,4-dioxin-2-yl)-5-{[(3-{[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]methyl}phenyl)methyl]amino}benzonitrile, ... (7 entities in total)
• 機能のキーワード: alpha glucosidase i, hydrolase, inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Thermochaetoides thermophila
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 189053.86

構造登録者

Karade, S.S.,Mariuzza, R.A. (登録日: 2022-10-06, 公開日: 2023-02-22, 最終更新日: 2024-10-09)

主引用文献

Karade, S.S.,Franco, E.J.,Rojas, A.C.,Hanrahan, K.C.,Kolesnikov, A.,Yu, W.,MacKerell Jr., A.D.,Hill, D.C.,Weber, D.J.,Brown, A.N.,Treston, A.M.,Mariuzza, R.A.
Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum alpha-Glucosidase I with Anti-SARS-CoV-2 Activity.
J.Med.Chem., 66:2744-2760, 2023

PubMed Abstract: Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.

PubMed: 36762932
DOI: 10.1021/acs.jmedchem.2c01750

実験手法

X-RAY DIFFRACTION (2.2 Å)