title: Design, synthesis, evaluation, and crystallographic-based structural studies of HIV-1 protease inhibitors with reduced response to the V82A mutation.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: José C
authors.initials: JC
authors.lastname: Clemente
authors.forename: Arthur
authors.initials: A
authors.lastname: Robbins
authors.forename: Paula
authors.initials: P
authors.lastname: Graña
authors.forename: M Rita
authors.initials: MR
authors.lastname: Paleo
authors.forename: Juan F
authors.initials: JF
authors.lastname: Correa
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Villaverde
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Sardina
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Govindasamy
authors.forename: Mavis
authors.initials: M
authors.lastname: Agbandje-McKenna
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.forename: Fredy
authors.initials: F
authors.lastname: Sussman
mesh_terms: D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D003510:Cyclohexanes; D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1