DFT and Docking Study of Potential Transition State Analogue Inhibitors of Glycosyltransferases

Abstract

Conformational behavior of the [(2S,3R,4R,5S)-3,4,5-trihydroxy-2-(phenylsulfanyl)tetrahydrofuran-2-yl]methyl sulfate anion (2), which is the potential transition state (TS) analogue of the inverting glycosyltransferases, was studied by means of two-dimensional potential-energy maps, using a density functional theory method at the B3LYP/6-31+G* level. The maps revealed the presence of eight low-energy domains which were refined at the B3LYP/6-311++G** level and led to six conformers in vacuum. In aqueous solution, two conformers dominate at equilibrium. The preferred conformers superimpose well with the transition state structure, as determined previously for glycosyltransferase GnT-I. The conformations of 2 in the active site of glycosyltransferase GnT-I were obtained by docking methods. It was found that one of the two best docking poses mimics the binding mode of TS. These results suggest that the proposed TS mimics 2 have the potential to be used as a scaffold for the design of TS analogue inhibitors.