کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1369852 981791 2016 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton’s tyrosine kinase inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton’s tyrosine kinase inhibitors
چکیده انگلیسی

A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton’s tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07 μM. The preliminary structure–activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 26, Issue 13, 1 July 2016, Pages 3052–3059
نویسندگان
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