PDBsum entry 6w4c

Oxidoreductase

PDB id: 6w4c

Contents

Protein chain

336 a.a.

Ligands

FMN

SL7

Waters ×203

PDB id:

6w4c

Name:

Oxidoreductase

Title:

Crystal structure of hao1 in complex with indazole acid inhibitor - compound 5

Structure:

Hydroxyacid oxidase 1. Chain: a. Synonym: haox1,glycolate oxidase,gox. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hao1, gox1, haox1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.75Å R-factor: 0.163 R-free: 0.193

Authors:

A.D.Ferguson

Key ref:

E.C.Y.Lee et al. (2021). Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening. J Med Chem, 64, 6730-6744. PubMed id: 33955740 DOI: 10.1021/acs.jmedchem.0c02271

Date:

10-Mar-20 Release date: 12-May-21

Protein chain

Q9UJM8  (HAOX1_HUMAN) -  2-Hydroxyacid oxidase 1 from Homo sapiens

Seq: 370 a.a.

Struc: 336 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.1.1.3.15 - (S)-2-hydroxy-acid oxidase.
• Reaction: a (2S)-2-hydroxycarboxylate + O2 = a 2-oxocarboxylate + H2O2
• Cofactor: FMN

FMN (Bound ligand (Het Group name = FMN) corresponds exactly)

• Enzyme class 2: E.C.1.2.3.5 - glyoxylate oxidase.
• Reaction: glyoxylate + O2 + H2O = oxalate + H2O2 + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.0c02271

J Med Chem 64:6730-6744 (2021)

PubMed id: 33955740

Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.

E.C.Y.Lee, A.J.McRiner, K.E.Georgiadis, J.Liu, Z.Wang, A.D.Ferguson, B.Levin, M.von Rechenberg, C.D.Hupp, M.I.Monteiro, A.D.Keefe, A.Olszewski, C.J.Eyermann, P.Centrella, Y.Liu, S.Arora, J.W.Cuozzo, Y.Zhang, M.A.Clark, C.Huguet, A.Kohlmann.

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 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, 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 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.