Kalsi A, Kavarana M J, Lu T, Whalen D L, Hamilton D S, Creighton D J
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
J Med Chem. 2000 Oct 19;43(21):3981-6. doi: 10.1021/jm000160l.
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.
疏水相互作用在将S-（N-芳基/烷基-N-羟基氨基甲酰基）谷胱甘肽与人类、酵母和恶臭假单胞菌乙二醛酶I的活性位点结合过程中发挥着重要作用，因为这些基于机制的竞争性抑制剂的log K(i)值会随着N-芳基/烷基取代基的疏水性常数（π）值增加而线性降低。疏水相互作用还有助于优化酶与谷胱甘肽衍生物之间的极性相互作用，因为S-（N-羟基氨基甲酰基）谷胱甘肽（π = 0）与人类酶的K(i)值比从log K(i)与π的关系图中得到的该化合物的内插值大35倍。计算研究与已发表的X射线晶体学测量结果相结合，表明人类乙二醛酶I结合S-（N-芳基-N-羟基氨基甲酰基）谷胱甘肽的顺式构象异构体，其中N-芳基取代基处于其最低能量构象。这些研究为开发针对这种抗肿瘤靶标酶的更好抑制剂提供了实验和概念框架。
