Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening
| العنوان: | Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening |
|---|---|
| المؤلفون: | Esther C. Y. Lee (10586857), Andrew J. McRiner (2512648), Katy E. Georgiadis (10756246), Julie Liu (6557627), Zooey Wang (10756249), Andrew D. Ferguson (1427719), Benjamin Levin (10185539), Moritz von Rechenberg (10586875), Christopher D. Hupp (2377594), Michael I. Monteiro (10586860), Anthony D. Keefe (3622769), Allison Olszewski (2671783), Charles J. Eyermann (1667878), Paolo Centrella (10756252), Yanbin Liu (231378), Shilpi Arora (130546), John W. Cuozzo (1665235), Ying Zhang (40767), Matthew A. Clark (1370337), Christelle Huguet (8932838), Anna Kohlmann (1417150) |
| سنة النشر: | 2021 |
| المجموعة: | Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: | Biochemistry, Cell Biology, Pharmacology, Ecology, Inorganic Chemistry, Hematology, Environmental Sciences not elsewhere classified, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Information Systems not elsewhere classified, DNA-Encoded Chemical Library Screen., SAR, carboxylic acid-containing compounds, hydroxy acid oxidase 1, DNA-Encoded Chemical Library, PK, PH, novel chemical series, non-acid-containing HAO 1 inhibitors, HAO 1 inhibitors, Compound 5, potency, AGXT, exploration, DECL, ADME, Structure-based drug design |
| الوصف: | 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. |
| نوع الوثيقة: | dataset |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/dataset/Discovery_of_Novel_Potent_Inhibitors_of_Hydroxy_Acid_Oxidase_1_HAO1_Using_DNA-Encoded_Chemical_Library_Screening/14547316 |
| DOI: | 10.1021/acs.jmedchem.0c02271.s003 |
| الاتاحة: | https://doi.org/10.1021/acs.jmedchem.0c02271.s003 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.92FB83B2 |
| قاعدة البيانات: | BASE |
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