Effects of Substituting a OH Group by a F Atom in d-Glucose. Ab Initio and DFT Analysis

Abstract

High-level ab initio and DFT methods up to MP2/6-311++G//B3LYP/6-31G and B3LYP/6-311++G//B3LYP/6-31G levels have been used to assess the relative energies of 17 different structures of D-glucose and 13 different structures of 4-deoxy-4-fluoro-D-glucose. The structures were confirmed to correspond to minima on the potential energy surface at the RHF/6-31G level. Solvation Model 5.4/AM1 was used to calculate the effects of aqueous solution. The substitution of a OH group by a F atom does not much change the shape and electrostatic potential around corresponding conformers, but in the gas phase it destabilizes the cooperative network of intramolecular hydrogen bonds. This destabilization mostly affects structures with a chain of intramolecular hydrogen bonds oriented counterclockwise, as fluorine is unable to donate a hydrogen bond and therefore causes a gap in the chain. In contrast, for clockwise-oriented networks of hydrogen bonds, the fluorine can act as an acceptor at the end of a chain of cooperative hydrogen bonds. A slightly higher energy of anomeric and exo-anomeric stabilization is another effect of substituting the fourth hydroxyl group by a fluorine atom in D-glucose, observed both in the gas phase and in aqueous solution. For this reason, the alpha anomers contribute more to the equilibrium population of structures of 4-deoxy-4-fluoro-D-glucose than D-glucose. In aqueous solution, both D-glucose and its 4-deoxy-4-fluoro analogue are present as a mixture of mainly three corresponding structures. This indicates that 4-deoxy-4-fluoro-D-glucose is a good substitute for D-glucose in terms of its biochemical and biological activity. Moreover, this suggests that, for molecules with limited conformational freedom, the substitution of a OH group by a F atom is very likely to lead to a potential new drug. In contrast, it had already been shown that, for conformationally labile aliphatic compounds, replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine-containing aliphatic molecules were not likely to be an example of a successful drug design. On the other hand, this work shows that, among molecules with limited conformational freedom, such as cyclic compounds, one is very likely to find targets for a successful rational drug design.

The interactome: Predicting the protein-protein interactions in cells

“…Proper selection of the protein domain is necessary [102][103][104][105][106][107][108]. In addition to pure chemical data [109][110][111][112][113][114][115][116] in the context of the Drug Discovery [117][118][119][120][121][122][123][124][125][126][127], there is also a need for some knowledge on protein-protein interactions, the high quality structural prediction of proteins [2,[128][129][130][131][132][133][134][135][136] and their inhibitors, and a detailed understanding of how those inhibitors affect the molecular recognition between proteins. The development of theoretical methods for function annotation clearly shows that a detailed analysis of local characteristics of the protein chain can significantly improve accuracy.…”

Imino Sugars Are Potent Agonists of the Human Glucose Sensor SGLT3

“…Substitution of the C4-OH with -F at the equatorial and axial positions did not significantly influence the interaction with hSGLT3, because the kinetics of 4D4Fglc Ϸ glucose, and neither 4D4Fgal nor galactose interacts with hSGLT3 (Table 1). The ability of -F to mimic the -OH at C4 may be the result of hydrogen bonding; however, recent evidence suggests organic -F is unlikely to participate in hydrogen bonds (Hoffmann and Rychlewski, 2001;Park et al, 2001;Biffinger et al, 2004;Dunitz, 2004). A possibility is the displacement of water molecules interacting with hSGLT3, which -F would do equally well as -OH.…”

Microwave Spectroscopy of Biomolecular Building Blocks

“…Finally, the structural analysis of D-glucose requires the consideration of intramolecular hydrogen bond networks involving adjacent OH groups. The orientation of the hydroxyl groups is relevant to distinguish between the different conformers of D-glucose and is thought to account for Apart from the number of theoretical studies on D-glucopyranose [257,258], only one vibrational spectroscopic study of α-D-glucopyranose isolated in Ar matrix has been reported [259]. Laser spectroscopy through UV-UV and IR-UV doubleresonance techniques has contributed to the description of the conformations of some β-phenylglucopyranosides and their hydrates [219,220,260,261] but these studies are limited to vibrational resolution and the structural conclusions are not totally transferable to D-glucose because of the electronic chromophore at the anomeric position.…”