Automated site-directed drug design: the concept of spacer skeletons for primary structure generation

Abstract

This paper examines the problem of automated structure generation at specified binding sites. The objective is to obtain molecular graphs that span the binding site and incorporate predicted ligand points at their vertices. Three approaches are considered: brute-force techniques, subgraph addition and spacer skeletons. Spacer skeletons are assemblies of molecular subgraphs and are used to reduce the combinatorial problems of structure generation to a practicable level for future analysis. This description is restricted to structure generation in two dimensions. Assemblies of rings are examined for planarity by searching the Cambridge Structural Database. Appropriate spacer skeletons may then be fitted to arrays of site points.