J. Frau et Sl. Price, ON THE ELECTROSTATIC AND STERIC SIMILARITY OF LACTAM COMPOUNDS AND THE NATURAL SUBSTRATE FOR BACTERIAL CELL-WALL BIOSYNTHESIS, Journal of computer-aided molecular design, 10(2), 1996, pp. 107-122
Electrostatic and structural properties of a set of beta-lactam, gamma
-lactam and nonlactam compounds have been analyzed and compared with t
hose of a model of the natural substrate D-alanyl-D-alanine for the ca
rboxy- and transpeptidase enzymes. This first comparison of the electr
ostatic properties has been based on a distributed multipole analysis
of high-quality ab initio wave functions of the substrate and potentia
l antibiotics. The electrostatic similarity of the substrate and activ
e compounds is apparent, and contrasts with the electrostatic properti
es of the noninhibitors. This has been quantified to give a reasonable
correlation with the MIC (Minimum Concentration for Inhibition) and w
ith kinetic data (k(2)/K) in accordance with the model for interaction
of the lactam compounds with DD-peptidase. These correlations provide
a better prediction of antibacterial activity than purely structural
criteria.