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 functi onal groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric bindi ng, the sulfamides seemed prone to bind nonsymmetrically, as deduced from X -ray crystal structure analysis of one of the most potent inhibitors, posse ssing ketoxime groups in the P2/P2' side chains. Ab initio calculations sug gested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conform ation.