Efficient overlay of small organic molecules using 3D pharmacophores

Gerhard Wolber, Alois A. Dornhofer, Thierry Langer

Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity measure when describing and analyzing macromolecule-ligand interaction. In this study, a novel approach for aligning rigid three-dimensional molecules according to their chemical-functional pharmacophoric features is presented and compared to the overlay of experimentally determined poses in a comparable macromolecule coordinate frame. The presented approach identifies optimal chemical feature pairs using distance and density characteristics obtained by correlating pharmacophoric geometries and thus proves to be faster than existing combinatorial alignment methods and creates more reasonable alignments than pure atom-based methods. Examples will be provided to demonstrate the feasibility, speed and intuitiveness of this method.