The matching of electrostatic extrema: A useful method in drug design? A study of phosphodiesterase III inhibitors

Summary Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multipole analysis of an ab initio charge density of the molecule, so that the effects of lone pair and -electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3,5-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.     

The set of mapsF_{a,b} :x \mapsto x + a + \tfrac{b}{{2\pi }} sin(2πx) with any given rotation interval is contractiblewith any given rotation interval is contractible

Consider the two-parameter family of real analytic maps $F_{a,b} :x \mapsto x + a + \tfrac{b}{{2\pi }}$ sin(2πx) which are lifts of degree one endomorphisms of the circle. The purpose of this paper is to provide a proof that for any closed intervalI, the set of mapsF _a,b whose rotation interval isI, form a contractible set.     

On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis

Summary Electrostatic and structural properties of a set of -lactam, -lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate d-alanyl-d-alanine for the carboxy- and transpeptidase enzymes. This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics. The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k₂/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.