Published in Bioorg. Med. Chem.. 2000, 8, 1881-1891

Alpha-ketoamides and alpha-ketocarbonyls: Conformational analysis and development of all-atom OPLS force field.

Kalju Kahn and Thomas C. Bruice

Abstract:

The molecular structures and barriers for the internal rotation around the OC---CO single bond in four alpha-ketoamides and eight alpha-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. alpha-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 alpha-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary alpha-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 alpha-ketoamide or alpha-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides.


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