5OJE

Endothiapepsin with Ligand VSK-B24

5OJE の概要

• エントリーDOI: 10.2210/pdb5oje/pdb
• 分子名称: Endothiapepsin, (2~{S})-2-azanyl-3-(1~{H}-indol-3-yl)-~{N}-[2-(2,4,6-trimethylphenyl)ethyl]propanamide, DIMETHYL SULFOXIDE, ... (7 entities in total)
• 機能のキーワード: protein templated dcc, bioisostere, inhibitor, endothiapepsin, peptide binding protein, hydrolase
• 由来する生物種: Cryphonectria parasitica (Chestnut blight fungus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34579.79

構造登録者

Gierse, R.M.,Magari, F.,Groves, M.R.,Heine, A.,Klebe, G.,Hirsch, A. (登録日: 2017-07-21, 公開日: 2018-09-12, 最終更新日: 2024-11-13)

主引用文献

Jumde, V.R.,Mondal, M.,Gierse, R.M.,Unver, M.Y.,Magari, F.,van Lier, R.C.W.,Heine, A.,Klebe, G.,Hirsch, A.K.H.
Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.
ChemMedChem, 13:2266-2270, 2018

PubMed Abstract: Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.

PubMed: 30178575
DOI: 10.1002/cmdc.201800446

実験手法

X-RAY DIFFRACTION (1.579 Å)