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 Ps eudomonas putida glyoxalase I, as the log K-i values for these mechanism-ba sed 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 a nd the glutathione derivatives, given that the K-i value for S-(N-hydroxyca rbamoyl)glutathione (pi = 0) with the human enzyme is 35-fold larger than t he interpolated value for this compound obtained from the log K-i versus pi plot. Computational studies, in combination with published X-ray crystallo graphic measurements, indicate that human glyoxalase I binds the syn-confor mer of S-(N-aryl-N-hydroxycarbamoyl)glutathione in which the N-aryl substit uents 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.