Conformational landscape and low lying excited states of imatinib

Abstract

The conformational changes of imatinib (IMT) are crucial for understanding the ligand-receptor interaction and its mechanism of action [Agofonov et al. (2014) Nature Struct Mol Biol 21:848-853]. Therefore, here we investigated the free energy conformational landscape of the free IMT base, aiming to describe the three-dimensional structures and energetic stability of its conformers. Forty-five unique conformers, within an energy window of 4.8 kcal mol −1 were identified by a conformational search in gas-phase, at the B3LYP/6-31G(d) theoretical level. Among these, the 20 most stable, as well as 4 conformers resulting from optimization of experimental structures found in the two known polymorphs of IMT and in the cAbl complex were further refined using the 6-31+G(d,p) basis set and the polarizable continuum solvation model. The most stable conformers in gas-phase and water exhibit a V-shaped structure. The major difference between the most stable free conformers and the bioactive conformers consists in the relative orientation of the pyrimidine-pyridine groups responsible for hydrogen bonding interactions in the ATP-binding pocket.The ratio of mole fractions corresponding to the two known (α and β) polymorphic forms of IMT was estimated from the calculated thermochemical data, in quantitative agreement with the existing experimental data related to their solubility. The electronic absorption spectrum of this compound was investigated in water and explained based on the theoretical TD-DFT results, considering the Boltzmann populationaveraged computed data at CAM-B3LYP/6-31+G(d,p) level of theory for the nine most stable conformers.

Molecular Structure of Phenytoin: NMR, UV-Vis and Quantum Chemical Calculations

“…In such cases, the calculated spectra must include the responses from all species, weighted by their Boltzmann factors. [45][46][47][48][49][50][51][52] For this reason we calculated the electronic absorption and NMR spectra of DPH considering the dimers with relative populations greater than 5 %.…”

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam

“…4 To name the conformers, we used the usual terminology in polymer stereochemistry. 74,75 More details on this nomenclature are given in the study by Vint¸eler et al 76 As in the case of piracetam, 77,78 by varying the torsion angle around the C10-C7 and C7-N1 single bonds, we obtained 14 conformers of 2 types, denoted by the second and third character as either GþGÀ or GÀAþ and 8 conformers of 6 types denoted (with the second and third characters) as AþGÀ, AÀGÀ, TGÀ, TT, AþT, or AÀAþ 79 (see Table 1 and Supplementary Table SI.2 in ESI).As shown in Figure 1, the conformers (1)- (6) are dominant, with a total Boltzmann relative population of 85.8% in gas phase and 89.5% in water. Compared to the gas-phase state, an important energetic rearrangement of the conformers is predicted in the 2 solvents, where conformers (5) and (6) become the most stabilized in water and ethanol, respectively.…”