Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 570 Life sciences Biology
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2017
• Mô tả vật lý: Size: p. 5816-5825 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260464
• Chủ đề: 1. 60 applied life sciences; 2. Crystal structure; 3. Inhibition; 4. Inhibitors; 5. Peptides and proteins; 6. X-rays

Tóm tắt

 We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13�inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn<
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  chelating unit was replaced with nonchelating polar residues that bridged over the Zn<
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  binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn<
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  ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.