In-solution conformational analysis of the XCYCH3 moiety for small esters and ethers with all combinations of X, Y = O, S.

Favorable steric and electrostatic fit of a ligand to a receptor is of central interest in theoretical drug design. This paper considers the effects of non-protic solvents, in comparison with the gas phase, on the preferred conformation of the XCYCH3 moiety of simple aliphatic esters and heterocyclic methyl ethers with all combinations of the X and Y atoms as oxygen and sulfur. An IEF-PCM/B97D/aug-cc-pv(t+d)z continuum dielectric solvent study in chloroform and acetonitrile explores the through-space polarization effect of the environment on the conformational preference, not affected by possible solute-solvent hydrogen bond formation. The inherently favored structure for the present molecules is important, since the hypothetical oxygen and sulfur lone-pairs point approximately in opposite directions in the cis conformation of esters, whereas the trans and gauche conformations for the methyl group in ethers define nearly parallel or perpendicular directionality for the lone pairs of the ring heteroatoms and the O or S atoms connecting to the ring. These different preferences for the studied two families of compounds allow for designing formation of hydrogen bonds with a protein in fairly different regions of the latter still within the ligand-binding cavity. For a fine-tuning of these hydrogen bonds, a replacement of an oxygen atom of the ligand by a sulfur atom could be a straightforward possibility.