J. Mol. Graph. & Model. 16, 150-156 (1998)


Similarity Studies on Guanidinium, Imidazolinium and Imidazolium Cations: Towards New Bradykinin Antagonists

Bradykinin (BK) is a potent nociceptive agent and its antagonists show analgesic activity. In the search for new antagonists of BK, the design of nonpeptidic derivatives with different terminal cations has been considered. Among these new antagonists, the guanidinium cations, which appear not only in the terminal arginine residues of BK but also in several nonpeptidic antagonists, will be substituted by groups with characteristics similar in terms of electrostatic potential, electron density, shape, etc. Several similarity indexes have been calculated for guanidinium, 2-aminoimidazolinium, and 2-aminoimidazolium cations and their corresponding neutral species to design new nonpeptidic BK antagonists. The geometric and electronic characteristics of the molecules were compared by means of: (1) the Carbo index, (2) the Hodgkin index, and (3) a shape similarity index based on the volume of each molecule as defined by a certain electron density. Molecular geometries and energies were optimized by ab initio calculations at the B3LYP/6-311++G∗∗ level. The molecular electrostatic potential (MEP) and the electron density (ρ) were then computed in a cubic grid of points around each molecule. These molecular properties were used to calculate similarity indexes with the guanidinium cation or guanidine as the reference molecule in each family. In addition, three-dimensional similarity maps were generated to localize those molecular areas more alike in each of the sets.