6W4C

Crystal structure of HAO1 in complex with indazole acid inhibitor - compound 5

6W4C の概要

• エントリーDOI: 10.2210/pdb6w4c/pdb
• 分子名称: Hydroxyacid oxidase 1, FLAVIN MONONUCLEOTIDE, 5-[[3-[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]-2-oxidanyl-phenyl]methylamino]-2~{H}-indazole-3-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41584.65

構造登録者

Ferguson, A.D. (登録日: 2020-03-10, 公開日: 2021-05-12, 最終更新日: 2023-10-18)

主引用文献

Lee, E.C.Y.,McRiner, A.J.,Georgiadis, K.E.,Liu, J.,Wang, Z.,Ferguson, A.D.,Levin, B.,von Rechenberg, M.,Hupp, C.D.,Monteiro, M.I.,Keefe, A.D.,Olszewski, A.,Eyermann, C.J.,Centrella, P.,Liu, Y.,Arora, S.,Cuozzo, J.W.,Zhang, Y.,Clark, M.A.,Huguet, C.,Kohlmann, A.
Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.
J.Med.Chem., 64:6730-6744, 2021

PubMed Abstract: Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds -. Compound was further optimized via various structure-activity relationship (SAR) exploration methods to , a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound led to the identification of a nonacid inhibitor of HAO1, , which has weaker potency and increased permeability.

PubMed: 33955740
DOI: 10.1021/acs.jmedchem.0c02271

実験手法

X-RAY DIFFRACTION (1.75 Å)