MOLECULAR SHAPE COMPARISON OF ANGIOTENSIN-II RECEPTOR ANTAGONISTS

A new and powerful analytical method for comparing molecular shapes by optimizing the overlap of molecular volumes has been developed. This shape comparison method provides both a quantitative measure of the sh ape similarity of molecules and a means to align molecules such that s hape similarity if maximized. Our MSC method has been enhanced with an option to allow discrimination between groups with different chemical properties. Atoms or groups of atoms may be assigned to different cla sses based on specific properties such as electrostatic potential, hyd rogen bonding ability, or hydrophobicity. This enables matches based o n criteria such as alignment of hydrophobic groups or hydrogen bond ac ceptor groups. In this study, we report shape comparisons of angiotens in II (AII) receptor antagonists from two structural classes, 4-(biphe nyl-4-ylmethoxy)-quinoline derivatives such as ICI D8731 and N-(biphen yl-4-ylmethyl)imidazole derivatives, such as DuP 753. Starting with a list of low-energy conformations for the two molecules, each conformat ion of the first molecule is paired with each of the conformations of the second molecule. For each of these conformational pairs, an MSC co mparison, which generates multiple MSC maxima, is initiated. Eight hig h scoring conformational pairings were found with shape matching based on the intersection of the total molecular volume, while nine high-sc oring pairs were identified with matching by atom type. MSC identifies conformational pairs with high shape similarity, as measured by the i ntersection volume, and thus generates and prioritizes several alterna tive models for the AII antagonist pharmacophore.