Role of hydrophobic interactions in binding S-(N-aryl/alkyl-N-hydroxycarbamoyl)glutathiones to the active site of the antitumor target enzyme glyoxalase I.
Hydrophobic interactions play an important role in binding S-(N-aryl/alkyl-N-hydroxycarbamoyl)glutathiones to the active sites of human, yeast, and Pseudomonas putida glyoxalase I, as the log K(i) values for these mechanism-based competitive inhibitors decrease linearly with increasing values of the hydrophobicity constants (pi) of the N-aryl/alkyl substituents. Hydrophobic interactions also help to optimize polar interactions between the enzyme and the glutathione derivatives, given that the K(i) value for S-(N-hydroxycarbamoyl)glutathione (pi = 0) with the human enzyme is 35-fold larger than the interpolated value for this compound obtained from the log K(i) versus pi plot. Computational studies, in combination with published X-ray crystallographic measurements, indicate that human glyoxalase I binds the syn-conformer of S-(N-aryl-N-hydroxycarbamoyl)glutathiones in which the N-aryl substituents are in their lowest-energy conformations. These studies provide both an experimental and a conceptual framework for developing better inhibitors of this antitumor target enzyme.
Kalsi
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A
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
Kavarana
M J
MJ
Lu
T
T
Whalen
D L
DL
Hamilton
D S
DS
Creighton
D J
DJ
D000970:Antineoplastic Agents / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry*; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D007791:Lactoylglutathione Lyase; D005978:Glutathione