CORRELATION OF BIOLOGICAL-ACTIVITY IN BETA-LACTAM ANTIBIOTICS WITH WOODWARD AND COHEN STRUCTURAL PARAMETERS - A CAMBRIDGE DATABASE STUDY

Biological activity in beta-lactam antibiotics has been correlated pre viously with one of two geometrical parameters, the Woodward height-of -pyramid, h, or the Cohen lactam O-atom to carboxylate C-atom distance , c. Here we describe a joint correlation of the two empirical paramet ers, h and c, with biological activity and the implications of such a correlation to enzyme-drug interactions in the beta-lactam class of an tibiotics, The Cambridge Structural Database (CSD) was the natural met hod of analysis and a substantial number of beta-lactam structures (11 4) has been examined. It has been found that molecules with either hig h h and high c values or low h and low c values correspond to active s keletons. In contrast, molecules with high h and low c or low h and hi gh c values are largely devoid of activity. The behaviour of outliers in both sets of populations has been explained on the basis of chemica l and stereochemical factors. This correlation is far superior to the correlation of biological activity based either on h or c alone. Such an observation, namely that activity is a multivariate phenomenon, hin ts that a third parameter, which could be a torsional parameter about a non-bonded vector, is probably a better indicator of activity, Using crystal structure information on the binding of beta-lactam antibioti cs to their target enzymes, transpeptidases and beta-lactamases, this parameter is shown to be an overall shape factor. The joint correlatio n of h and c parameters with biological activity provides a better und erstanding of structure-activity relationships and should find applica tion in the rational discovery of new beta-lactam antibiotics.