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 Kiof 0.025 nM and antiviral IC50of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Ã resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Ã resolution. These structures revealed important molecular insight into the inhibitorâHIV-1 protease interactions in the active site.
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|Titolo:||Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex|
|Appare nelle tipologie:||1.1 Articolo in rivista|