Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains.
Symmetric cyclic sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.
Hultén
J
J
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Andersson
H O
HO
Schaal
W
W
Danielson
H U
HU
Classon
B
B
Kvarnström
I
I
Karlén
A
A
Unge
T
T
Samuelsson
B
B
Hallberg
A
A
D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010671:Phenylurea Compounds / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013449:Sulfonamides / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D010671:Phenylurea Compounds; D013449:Sulfonamides; D016333:HIV Protease