-Ketoamides and -Ketocarbonyls: Conformational Analysis and Development of All-Atom OPLS Force Field

ÐThe molecular structures and barriers for the internal rotation around the OCÿCO single bond in four a-ketoamides and eight a-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. a-Ketocarbonyls with non-bulky substituents adopt planar conformations with two carbonyl oxygens in s-trans arrangement. The s-cis conformation is signi®cantly less stable due to the electrostatic repulsion between the two carbonyl groups. Primary and secondary a-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary a-ketoamides adopt a conformation where the OCÿCO unit is signi®cantly bent. Based on current ab initio structural data, a set of OPLSÿAA force ®eld parameters has been derived. These parameters can be used for the modeling of a variety of a-ketoamide or a-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides. # 2000 Elsevier Science Ltd. All rights reserved.