Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands [electronic resource] : Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.9792 Other diseases
• 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. 5114-5127 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260565
• Chủ đề: 1. 60 applied life sciences; 2. Drug-resistance; 3. Hiv-1 protease; 4. Isophthalamide; 5. Synthesis; 6. X-ray structure

Tóm tắt

 Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme K<
 sub>
 i<
 /sub>
  of 0.025 nM and antiviral IC<
 sub>
 50<
 /sub>
  of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 � resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 � resolution. Furthermore, these structures revealed important molecular insight into the inhibitor?HIV-1 protease interactions in the active site.