Potential transition-state analogs for glycosyltransferases. Design and DFT calculations of conformational behavior |
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Authors: | Raab Michal Kozmon Stanislav Tvaroska Igor |
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Affiliation: | Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia. |
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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. |
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Keywords: | Glycosyltransferases Transition-state analog Inhibitors Conformation Density functional Ab initio calculations |
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