8RX7 の概要
| エントリーDOI | 10.2210/pdb8rx7/pdb |
| 関連するPDBエントリー | 8RX3 |
| 分子名称 | Leukotriene A-4 hydrolase, ZINC ION, ACETATE ION, ... (7 entities in total) |
| 機能のキーワード | lta4h, inhibitor, hydrolase |
| 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 | 70288.96 |
| 構造登録者 | |
| 主引用文献 | Thoma, G.,Miltz, W.,Srinivas, H.,Penno, C.A.,Kiffe, M.,Gajewska, M.,Klein, K.,Evans, A.,Beerli, C.,Rohn, T.A. Structure-Guided Elaboration of a Fragment-Like Hit into an Orally Efficacious Leukotriene A4 Hydrolase Inhibitor. J.Med.Chem., 67:5093-5108, 2024 Cited by PubMed Abstract: Leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB). Preclinical studies have provided strong evidence that LTA4H is an attractive drug target for the treatment of chronic inflammatory diseases. Here, we describe the transformation of compound , a fragment-like hit, into the potent inhibitor of LTA4H . Our strategy involved two key steps. First, we aimed to increase the polarity of fragment to improve its drug-likeness, particularly its solubility, while preserving both its promising potency and low molecular weight. Second, we utilized structural information and incorporated a basic amino function, which allowed for the formation of an essential hydrogen bond with Q136 of LTA4H and consequently enhanced the potency. Compound exhibited exceptional selectivity and showed oral efficacy in a KRN passive serum-induced arthritis model in mice. The anticipated human dose to achieve 90% target engagement at the trough concentration was determined to be 40 mg administered once daily. PubMed: 38476002DOI: 10.1021/acs.jmedchem.4c00290 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.85 Å) |
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