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 20most stable, as well as 4
conformers resulting from optimization of experimental structures
found in the two known polymorphs of IMTand 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 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
