3D database searching and de novo construction methods in molecular design

Computer-based lead finding algorithms which attempt to design, on a de novo basis, ligands that will complement a known receptor site cavity face some major problems in terms of a combinatorial design space and the synthesizability of the designed molecules. On the other hand, typical 3D database search methods provide a different set of challenges. Both of these approaches are ultimately pointed toward the same goal and can be used together productively. In this article we describe advances in both areas: we first describe extensions to our de novo ligand design software which combines (a) a tree-based conformational search over a library of fragments, and (b) a form of simulated annealing which allows designed ligands to crawl around the binding site even as their structures are changing. In the second part, we then discuss an implementation of the database approach which allows users to formulate 3D substructure, superstructure, or similarity queries based upon demonstrated or hypothetical requirements for activity. Finally, we draw the two approaches together with an example of current research interest, showing how one method can feed the other.