Towards dynamic drug design: identification and optimization of beta-galactosidase inhibitors from a dynamic hemithioacetal system.
A discovery strategy relying on the identification of fragments through resolution of a constitutional dynamic system, coupled to subsequent static ligand design and optimization, is demonstrated. The strategic design and synthesis of the best molecular fragments identified from a dynamic hemithioacetal system into static ligand structures yielded a range of beta-galactosidase inhibitors. Two series of structures mimicking the hemithioacetal motif were envisaged: thioglycosides and C-glycosides. Inhibition studies provided important structural information for the two groups, and 1-thiobenzyl-beta-D-galactopyranoside demonstrated the best inhibitory effects.
Caraballo
Rémi
R
Department of Organic Chemistry, KTH-Royal Institute of Technology, Teknikringen 30, 10044 Stockholm, Sweden.
Sakulsombat
Morakot
M
Ramström
Olof
O
D015195:Drug Design; D006027:Glycosides; D006801:Humans; D008024:Ligands; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013865:Thioglycosides / Q000737:chemistry / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors*
C438934:C-glycoside; D006027:Glycosides; D008024:Ligands; D009005:Monosaccharides; D013865:Thioglycosides; D001616:beta-Galactosidase