Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam.

The analysis of the possible conformers and the conformational change between solid and liquid states of a particular drug molecule are mandatory not only for describing reliably its spectroscopical properties but also for understanding the interaction with the receptor and its mechanism of action. Therefore, here we investigated the free-energy conformational landscape of levetiracetam (LEV) in gas phase as well as in water and ethanol, aiming to describe the 3-dimensional structure and energetic stability of its conformers. Twenty-two unique conformers were identified, and their energetic stability was determined at density functional theory B3LYP/6-31+G(2d,2p) level of theory. The 6 most stable monomers in water, within a relative free-energy window of 0.71 kcal mol-1 and clearly separated in energy from the remaining subset of 16 conformers, as well as the 3 most stable dimers were then used to compute the Boltzmann populations-averaged UV-Vis and NMR spectra of LEV. The conformational landscape in solution is distinctly different from that corresponding to gas phase, particularly due to the relative orientations of the butanamide group. Aiming to clarify the stability of the possible dimers of LEV, we also investigated computationally the structure of a set of 11 nonhydrated and hydrated homochiral hydrogen-bonded LEV dimers.

Conformational landscape and low lying excited states of imatinib.

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 c-Abl 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 ß) 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 population-averaged computed data at CAM-B3LYP/6-31+G(d,p) level of theory for the nine most stable conformers.