The use of local surface properties for molecular superimposition.

This study employed surface-based properties for use in the superimposition of three series of molecules. The properties used were derived from semiempirical molecular orbital calculations and can be related to the physics of intermolecular interactions. In each case, the superimposition of the compounds was within 0.6 A of the experimental overlay. The superimposition cases presented differing levels of involvement of electrostatic interactions, and in only one case did shape similarity provide the best overlay. Two test compounds were applied to an example exploring non-nucleoside HIV-1 reverse transcriptase inhibitors and only one of these compounds overlaid in the same manner as their crystal structure complexes. This served to highlight the need for molecules to occupy the same region of space when employing this technique. Nevertheless, the method can be used to generate pharmacophores and ultimately could be used to interrogate databases for molecules that match the key surface properties, thus allowing scaffold hopping.