Conformational landscape and low lying excited states of imatinib

Journal of Molecular Modeling
Emil VinţelerVasile Chiş

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 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 ...Continue Reading

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Citations

Jul 29, 2016·PloS One·Priscila Da Silva Figueiredo Celestino GomesLuba Tchertanov
Jun 15, 2021·Journal of Biomolecular Structure & Dynamics·Washington A PereiraJoão B L Martins

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