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

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journal contribution
posted on 2008-02-28, 00:00 authored by José C. Clemente, Arthur Robbins, Paula Graña, M. Rita Paleo, Juan F. Correa, M. Carmen Villaverde, F. Javier Sardina, Lakshmanan Govindasamy, Mavis Agbandje-McKenna, Robert McKenna, Ben M. Dunn, Fredy Sussman
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.