Patent ID: 6415234
Filing Date: 2002-07-02
Classification: C07H

Abstract:
A computer-implemented method for designing potential inhibitors of a glycosyltransferases comprising:A. designing a nucleotide-sugar with a monophosphate linkage by (a) selecting a molecule comprising a first sugar, a phosphate group, and a second sugar that is transferred by the glycosyltransferase to an acceptor for the glycosyltransferase, wherein there is a bond between a carbon atom of the first sugar and a first oxygen atom of the phosphate group, and a linkage between a carbon atom of the second sugar and a second oxygen atom of the phosphate group, (b) optimizing the orientation of the molecule using ab initio quantum chemistry methods so that the orientation of the linkage is antiperiplanar; B. designing a nucleotide-sugar with a monophosphate linkage and having an electrostatic interaction between free oxygen atoms of the monophosphate and an ion by (a) selecting a molecule comprising a first sugar, a phosphate, and a second sugar that is transferred by the glycosyltransferase to an acceptor for the glycosyltransferase, wherein there is a bond between a carbon atom of the first sugar and a first oxygen atom of the phosphate group, a linkage between a carbon atom of the second sugar and a second oxygen atom of the phosphate group, and an electrostatic interaction between free oxygen atoms of the phosphate group and the ion, (b) optimizing the orientation of the molecule using ab initio quantum chemistry methods so that the orientation of the linkage is synclinal; C. designing a nucleotide-sugar with a diphosphate linkage by (a) selecting a molecule comprising a first sugar, a diphosphate group, and a second sugar that is transferred by the glycosyltransferase to an acceptor for the glycosyltransferase, and wherein there is a bond between a carbon atom of the first sugar and an oxygen atom of a first phosphate of the diphosphate group, and a linkage between a carbon atom of the second sugar and an oxygen atom of a second phosphate of the diphosphate group, and (b) optimizing the conformation of the molecule using ab initio quantum chemistry methods so that the orientation of the linkage is antiperiplanar, and phosphorous-oxygen bonds linking the first phosphate to the second phosphate of the diphosphate group are in a synclinal or anticlinal orientation, and synclinal orientation, respectively, or symmetrically related orientations; or D. designing a nucleotide-sugar with a diphosphate linkage and having an electrostatic interaction between free oxygen atoms of the diphosphate and the ion by (a) selecting a molecule comprising a first sugar, a diphosphate group, an ion, and a second sugar that is transferred by the glycosyltransferase to an acceptor for the glycosyltransferase, wherein there is a bond between a carbon atom of the first sugar and an oxygen atom of a first phosphate of the diphosphate group, a linkage between a carbon atom of the second sugar and an oxygen atom of a second phosphate of the diphosphate group, and an electrostatic interaction between two or more free oxygen atoms of the diphosphate group and the ion, (b) optimizing the conformation of the molecule using ab initio quantum chemistry methods so that the orientation of the linkage is synclinal, phosphorous-oxygen bonds linking the first phosphate to the second phosphate of the diphosphate group are in antiperiplanar or -anticlinal orientation, and synclinal orientation, respectively, or symmetrically related orientations.