α-Ketoamides and α-Ketocarbonyls: Conformational analysis and development of all-atom OPLS force field Original Research Article

The molecular structures and barriers for the internal rotation around the OCCO single bond in four α-ketoamides and eight α-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. α-Ketocarbonyls with non-bulky substituents adopt planar conformations with two carbonyl oxygens in s-trans arrangement. The s-cis conformation is significantly less stable due to the electrostatic repulsion between the two carbonyl groups. Primary and secondary α-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary α-ketoamides adopt a conformation where the OCCO unit is significantly bent. Based on current ab initio structural data, a set of OPLSAA force field parameters has been derived. These parameters can be used for the modeling of a variety of α-ketoamide or α-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides.