Thermodynamic conformational analysis and structural stability of the nicotinic analgesic ABT-594

This work presents a theoretical study of the nicotinic analgesic ABT-594. We describe its neutral (precursor) and protonated (active) forms in vacuum and aqueous solution at the MP2/cc-pVDZ level. A conformational analysis is performed on the two torsional angles describing the orientation of the azetidinyl group and the azetidinylmethoxy moiety. To account for entropic effects, a thermostatistical study of conformational populations at physiological temperature is carried out. In the neutral form, conformer I is found as the most populated in vacuum and solution. Here, the nitrogen of the azetidinyl group is far from the electron pairs of the oxygen and the pyridinic nitrogen. In the protonated form, conformer VIII is the most stable in vacuum and solution. Now, the additional proton on the azetidinyl group is oriented toward the electron lone pairs of oxygen. The structural stability of conformers I and VIII is considered through the atoms in molecules theory. The conformer I, in the neutral forms, is stabilized by an intramolecular hydrogen bond. The preference of conformer VIII in the protonated forms is explained by the higher strength of its intramolecular hydrogen bond over the cation-pi interaction found in conformer I. The effect of the interaction energy with the receptor on the conformational preferences of protonated ABT-594 is simulated. The result is that the population of conformers associated to the rotation of the azetidinyl group increases. So, the molecule can easily adopt the optimal internitrogen separation for interaction with the receptor.