Design, Synthesis, Evaluation, and Crystallographic-Based Structural Studies of HIV-1 Protease Inhibitors with Reduced Response to the V82A Mutation
In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 959536
- Report Number(s):
- BNL-82522-2009-JA; JMCMAR; TRN: US201016%%680
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 51; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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