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
Journal Article
·
· Bioorganic and Medicinal Chemistry
- Purdue Univ., West Lafayette, IN (United States)
- Georgia State Univ., Atlanta, GA (United States)
- Kumamoto Univ. of Medicine (Japan)
- Kumamoto Univ. of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
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 Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. Furthermore, these structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health
- Grant/Contract Number:
- W-31-109-Eng-38; GM53386; GM62920
- OSTI ID:
- 1418041
- Alternate ID(s):
- OSTI ID: 1495866
- Journal Information:
- Bioorganic and Medicinal Chemistry, Vol. 25, Issue 19; ISSN 0968-0896
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Cited by: 13 works
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