کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1357852 981300 2014 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structural insights into binding of inhibitors to soluble epoxide hydrolase gained by fragment screening and X-ray crystallography
ترجمه فارسی عنوان
بینش ساختاری به اتصال مهارکننده ها به هیدرولاز اپوکسی محلول حاصل از غربالگری قطعه و کریستالوگرافی اشعه ایکس
کلمات کلیدی
رویکرد مبتنی بر قطعه، ساختار کریستالی، لیگاند اتصال، فشار خون، التهاب طراحی دارو مبتنی بر ساختار، کریستالوگرافی پروتئین بالا
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
چکیده انگلیسی

Soluble epoxide hydrolase (sEH) is a component of the arachidonic acid cascade and is a candidate target for therapies for hypertension or inflammation. Although many sEH inhibitors are available, their scaffolds are not structurally diverse, and knowledge of their specific interactions with sEH is limited. To obtain detailed structural information about protein–ligand interactions, we conducted fragment screening of sEH, analyzed the fragments using high-throughput X-ray crystallography, and determined 126 fragment-bound structures at high resolution. Aminothiazole and benzimidazole derivatives were identified as novel scaffolds that bind to the catalytic triad of sEH with good ligand efficiency. We further identified fragment hits that bound to subpockets of sEH called the short and long branches. The water molecule conserved in the structure plays an important role in binding to the long branch, whereas Asp496 and the main chain of Phe497 form hydrogen bonds with fragment hits in the short branch. Fragment hits and their crystal structures provide structural insights into ligand binding to sEH that will facilitate the discovery of novel and potent inhibitors of sEH.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 8, 15 April 2014, Pages 2427–2434
نویسندگان
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