6W4C
Crystal structure of HAO1 in complex with indazole acid inhibitor - compound 5
Summary for 6W4C
| Entry DOI | 10.2210/pdb6w4c/pdb |
| Descriptor | 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) |
| Functional Keywords | inhibitor, complex, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41584.65 |
| Authors | Ferguson, A.D. (deposition date: 2020-03-10, release date: 2021-05-12, Last modification date: 2023-10-18) |
| Primary citation | 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 Cited by 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: 33955740DOI: 10.1021/acs.jmedchem.0c02271 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
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