title: Potential transition-state analogs for glycosyltransferases. Design and DFT calculations of conformational behavior.
abstract: The structure of a previously calculated transition state (TS) was used to design the [tetrahydro-2-(methylthio)furan-2-yl]methyl phosphate dianion (1) as a new scaffold for transition-state analogs of reactions catalyzed by the inverting glycosyltransferases. This scaffold contains relevant features of the donor and acceptor and represents a new type of potential inhibitors for these enzymes. Available conformational space of 1 was explored using DFT quantum chemical methods by means of two-dimensional potential-energy maps calculated as a function of Phi, Psi, and omega dihedral angles at the B3LYP/6-31+G* level. The calculated potential energy surfaces revealed the existence of several low-energy domains. Structures from these regions were refined at the 6-311++G** level and led to 14 conformers. The stability of conformers is influenced by their environment, and in aqueous solution two conformers dominate the equilibrium. A superposition of calculated conformers with the predicted TS structure revealed that the preferred conformers in solution nicely mimic structural features of the TS. These results imply that 1 has structural properties required to mimic the TS and therefore can be used as a scaffold for further development of TS-analog inhibitors for retaining glycosyltransferases.
authors.affiliation: Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Raab
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kozmon
authors.forename: Igor
authors.initials: I
authors.lastname: Tvaroska
mesh_terms: D003198:Computer Simulation; D005663:Furans / Q000737:chemistry*; D016695:Glycosyltransferases / Q000378:metabolism*; D008968:Molecular Conformation; D010755:Organophosphates / Q000737:chemistry*
chemical_list: C505395:(tetrahydro-2-(methylthio)furan-2-yl)methyl phosphate; D005663:Furans; D010755:Organophosphates; D016695:Glycosyltransferases