Techniques for Searching Databases of Three-Dimensional (3D) Structures with Receptor-Based Queries

Ligand-based vs. Receptor-based 3D Searching
A key concept in 3D searching is the pharmacophore. The term, introduced by Ehrlich in the early 1900s , refers to the molecular framework that carries (phoros) the essential features responsible for a drug's (pharmacon) biological activity. In the current literature, the term has been expanded to refer to the 3D arrangement of functional groups that enable a compound to exert a particular biological effect. Due to stereochemical considerations (i.e., three-point attachments), many pharmacophores are defined simply in terms of three atoms and three distances. If more information is available, other geometric objects and constraints can be added, including constraints on data associated with atoms and bonds . Presently, most pharmacophores are defined in terms of the atoms and bonds of the ligand structures. This ligand-based definition has advantages for input and searching purposes; in the case where the structure of the receptor is completely unknown, it is the only way one can effectively define a pharmacophore model.
It is clear that drugs that bind to a common receptor do not necessarily bind with similar functional groups precisely overlapped; rather, these drugs may show multiple modes of binding . The interactions between a drug molecule and a receptor can be dispersed and nonspecific, as in steric and lipophilic interactions - which nevertheless account for most of the free energy changes in binding . Alternatively, they can be highly specific and directional, such as interactions involving H-bond donors and acceptors or those with bound metal ions. But even then, precise overlap of heteroatoms may not result, since the specific interactions occur over a range of angles, distances, and energies .
Clearly, in such cases, a receptor-based approach to a pharmacophore definition is needed to carry key features of the receptor involved in drug molecule binding. A full receptor-based pharmacophore model complements the ligand-based pharmacophore model for the same activity; it is the 'lock' for a given 'key.' This concept has been expressed and utilized previously, as in the extended molecule approach of Andrews . Our purpose is to show how to implement receptor-based queries in a pharmacophore-based 3D search system. We will also evaluate the success of these queries with respect to their pharmacophoric counterparts by testing them on a database of drugs with known activities.