Document Report Card

ID: ALA1143243

Journal: J Med Chem

Title: Design, synthesis, evaluation, and crystallographic-based structural studies of HIV-1 protease inhibitors with reduced response to the V82A mutation.

Authors: Clemente JC, Robbins A, Graña P, Paleo MR, Correa JF, Villaverde MC, Sardina FJ, Govindasamy L, Agbandje-McKenna M, McKenna R, Dunn BM, Sussman F.

Abstract: 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.

CiteXplore: 18215016

DOI: 10.1021/jm701170f