Tautomeric preferences of the cis and trans isomers of axitinib

The tautomeric preferences of axitinib, a potent anticancer drug, as tyrosine kinase inhibitor have been investigated using quantum chemical calculations and docking methods. The energy differences between the two tautomers of trans-isomer are around 4 and 3 kcal mol(-1) in vacuo and water, respectively, and for its cis-isomer (major photochemical isomerization product) this equilibrium reversed completely in favour of the second tautomer (not considered previously), which is about 7-8 kcal mol(-1) more stable in both gas and aqueous media. The results indicate a very high activation energy for proton exchange for both [1,2] and [1,5] H-shift (around 50 kcal mol(-1)) in the gas phase, but inclusion of protic solvents (e.g. water) decrease this barrier to around 14 and 35 kcal mol(-1) for the both hydrogen shift processes, respectively. In order to have better insight about the electronic structure of axitinib tautomers, the NBO, HOMO-LUMO, NICS and molecular electrostatic potential surfaces (MESP) calculations have been carried out. Docking investigations on the two more stable tautomers revealed that binding of the trans isomer of tautomer I to the active site of the receptor is the most favourable in the terms of energy and structure. This more stability could be attributed to the more hydrogen bonding of this tautomer with the protein residues in comparison to the second tautomer. (C) 2018 Elsevier B.V. All rights reserved.