Tautomerism of Xanthine Oxidase Substrates Hypoxanthine and Allopurinol

Abstract

The tautomerism of neutral hypoxanthine and allopurinol in the gas phase and in aqueous solution has been examined by theoretical methods. The tautomeric equilibrium in the gas phase was studied from semiempirical and ab initio quantum mechanics (QM) and also from density functional theory (DFT) calculations. Electron correlation effects were included in ab initio computations at the Møller−Plesset level, and DFT calculations were carried out using the Becke3−Lee−Yang−Parr functional. The influence of the solvent was examined from self-consistent reaction field calculations performed with different continuum models. The results provide a detailed picture of the tautomerism of these biologically relevant compounds. Comparison with available experimental data provides support for the quality of results derived from theoretical computations. Inspection of the most stable tautomeric forms allows discussion of the functional implications of tautomerism for recognition and binding of these molecules to xanthine oxidase.

Theoretical study of valance photoelectron spectra of hypoxanthine, xanthine, and caffeine using direct symmetry‐adapted cluster/configuration interaction methodology

“…Theoretical and experimental observations have shown that the keto form predominates in the gas phase. 5,7,9,10,[21][22][23] For example, the valance photoelectron spectra of HYP, XAN, and CAFF, recorded by Feyer et al 9 at 100 eV photon energy are similar. Considering that CAFF has a single keto tautomer form, it can be concluded that this form is more stable in the gas phase, for HYP and XAN.…”

“…Additionally, highly expensive ab initio calculations have shown that the amount of enol tautomers is negligible in comparison with keto forms for HYP and XAN in gas phase. [21][22][23] In this work and based on the above observations, the keto tautomers of each compound have been considered for direct SAC-CI calculations.…”

“…This temperature was selected according to previous reports (530 K, spectrum e and f; 508 K, spectrum d), and the average temperature was used to calculate the Gibbs free energies and Boltzmann population ratios of the two tautomers. Notably, Shukla et al, 21 Ramaekers et al, 22 and Hernandez et al 23 also reported the thermodynamic stability and percentages of HYP tautomers that were calculated at different theory levels and basis sets at 298 K. However, we decided to use the same basis set for Gibbs free energy and SAC-CI calculations in this work.…”

A DFT Study of Solvation Effects on Tautomerism of 6-oxo Purine by Polarisable Continuum Method (PCM)

“…This conclusion is supported by results of UV 19,21 , IR 17,18 , Raman 29 , 1H NMR 19 and 13C NMR 19,23 spectroscopies, and X-ray analysis 24 . Pullman and Pullman 28 have investigated the tautomerism of oxopurines by the theoretical CNDO/2 method and three groups of authors [29][30][31] have reported ab initio quantum mechanical calculations using 6-31G(d), 6-31G(d,p), or MIDI basis sets. Contreras and Alderete 32 used the semiempirical AM1 and MNDO methods to calculate the structure, bondorder matrices, localized MOs, and IR spectra for the tautomers of hypoxanthine in the gas phase.…”

“…In addition, knowing how these tautomerization energies change in different environments can provide insight into the influence of solvent effects on molecular stability. The physicochemical properties of the tautomerism of hypoxanthine have been investigated experimentally [17][18][19][20][21][22][23][24][25][26][27] and theoretically [28][29][30][31][32] . In a wide variety of environments, including the gas phase, keto tautomers of hypoxan thine are most stable.…”