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 shape similarity of molecules and a means to align molecules such that shape 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 classes based on specific properties such as electrostatic potential, hydrogen bonding ability, or hydrophobicity. This enables matches based on criteria such as alignment of hydrophobic groups or hydrogen bond acceptor groups. In this study, we report shape comparisons of angiotensin II (AII) receptor antagonists from two structural classes, 4-(biphenyl-4-ylmethoxy)-quinoline derivatives such as ICI D8731 and N-(biphenyl-4-ylmethyl)imidazole derivatives, such as DuP753. Starting with a list of low-energy conformations for the two molecules, each conformation of the first molecule is paired with each of the conformations of the second molecule. For each of these conformational pairs, an MSC comparison, which generates multiple MSC maxima, is initiated. Eight high scoring conformational pairings were found with shape matching based on the intersection of the total molecular volume, while nine high-scoring pairs were identified with matching by atom type. MSC identifies conformational pairs with high shape similarity, as measured by the intersection volume, and thus generates and prioritizes several alternative models for the AII antagonist pharmacophore.

A novel analytical method for comparing molecular shapes by optimizing the intersection of molecular "SKINS" has been developed. This method provides a quantitative measure of the shape similarity by maximizing the intersection volume of molecular surfaces with a finite thickness; a molecular skin. We report shape matching of a small tripeptide inhibitor (DFKi) of elastase class proteins with the 56 residue turkey ovomucoid inhibitor (TOMI). To match a large elastase inhibitor such as TOMI with a small inhibitor or drug, we found that it is necessary to use a skin match rather than molecular volume. Skin based comparisons of TOMI protein with DFKi successfully found the alignment expected from comparison of their respective crystallographic complexes with elastase (i.e. HLE/TOMI complex and PPE/tripeptide complex). In the skin comparison of the tripeptide with the TOMI protein, blind searching for skin matches involved optimization of the skin intersection from 172 starting positions randomly selected from a set of 500 points on the TOMI van der Waals surface [within 9.5 A of the Leu-18 on the TOMI binding loop (1 point/A2)]. The tripeptide center of mass was placed at these points and its orientation was randomized before optimization was initiated. The best skin intersection, 86.4 A3, was found three times and corresponds to the experimental alignment. The next best skin intersection was 78.1 A3 giving a discrimination factor in this case of 10%. Searches over the entire surface of the TOMI protein did not identify any new matches with skin intersection greater than 78.1 A3. Matching the DFKi with a TOMI structure relaxed from its crystal conformation by molecular dynamics gives similar results.