کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1359116 981384 2010 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1′ pocket and their quantitative structure–activity relationship (QSAR) study
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1′ pocket and their quantitative structure–activity relationship (QSAR) study
چکیده انگلیسی

A series of coumarin based TACE inhibitors were designed to bind in S1′ pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure–activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1′ pocket and the TACE inhibitory activity well.

A series of chromen-based TACE inhibitors were designed to bind in S1′ pocket of TACE enzyme based on their docking study. The newly prepared analogues were evaluated in vitro assays and the most potent inhibitor (15l) was evaluated in pharmacokinetic model and in vivo pharmacological model. QSAR equation of the chromen-based TACE inhibitors is reliable in internal and external test set and its docking study confirms the equation.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 24, 15 December 2010, Pages 8618–8629
نویسندگان
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