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.
Clemente
José C
JC
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Robbins
Arthur
A
Graña
Paula
P
Paleo
M Rita
MR
Correa
Juan F
JF
Villaverde
M Carmen
MC
Sardina
F Javier
FJ
Govindasamy
Lakshmanan
L
Agbandje-McKenna
Mavis
M
McKenna
Robert
R
Dunn
Ben M
BM
Sussman
Fredy
F
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
D003510:Cyclohexanes; D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1