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

Abstract

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 multiple analysis of an ab initio charge density of the molecule, so that the effects of lone pair and pi-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.

Quantum chemical analysis of the interactions of transition state analogs with leucine aminopeptidase

“…Our nonempirical results indicate the dominant role of the electrostatic interactions, which correlate well with the experimental activities, although the magnitude of the remaining terms, exchange, delocalization, electrostatic penetration, and correlation, seems to be non‐negligible. Our analysis validates earlier observations indicating the essential role of electrostatic effects in inhibitory activity 5, 25–29.…”

Limiting assumptions in molecular modeling: electrostatics

“…This led to a relevant method for comparing molecules [49] based on the extrema (Fig. 3) in their electrostatic potentials [9,50]. In many ways, this approach is philosophically similar to the field comparisons available from CoMFA [51] and GRID [52] leading to subsequent approaches such as COMBINE [53,54] and COMBINEr [55,56].…”

Molecular Field Extrema as Descriptors of Biological Activity: Definition and Validation

“…In this paper, we revisit the approach that has utilized molecular field extrema [16][17][18][19] as a means of overcoming grid restrictions and large numbers of descriptors. We will describe the field generation and overlay procedures, how field patterns describe the nonbonding chemistry of ligands, and the results of simple overlay experiments.…”