Design, Synthesis, Evaluation, and Crystallographic-Based Structural Studies of HIV-1 Protease Inhibitors with Reduced Response to the V82A Mutation

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm701170f· OSTI ID:959536

Clemente, J; Robbins, A; Grana, P; Paleo, M; Correa, J; Villaverde, M; Sardina, F; Govindasamy, L; Agbandje-McKenna, M

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 Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959536
• Report Number(s): BNL--82522-2009-JA
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Vol. 51; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
AFFINITY
CHAINS
CYCLOHEXANE
DESIGN
EVALUATION
MUTATIONS
SYNTHESIS
national synchrotron light source