Protocols for bridging the peptide to nonpeptide gap in topological similarity searches

Similarity searches based on chemical descriptors have proven extremely use ful in aiding large-scale drug screening. Typically an investigator starts with a "probe", a drug-like molecule with an interesting biological activit y, and searches a database to find similar compounds. In some projects, how ever, the only known actives are peptides, and the investigator needs to id entify drug-like actives. 3D similarity methods are able to help in this en deavor but suffer from the necessity of having to specify the active confor mation of the probe, something that is not always possible at the beginning of a project. Also, 3D methods are slow and are complicated by the need to generate low-energy conformations. In contrast, topological methods are re latively rapid and do not depend on conformation. However, unmodified topol ogical similarity methods, given a peptide probe, will preferentially selec t other peptides from a database. In this paper we show some simple protoco ls that, if used with a standard topological similarity search method, are sufficient to select nonpeptide actives given a peptide probe. We demonstra te these protocols by using 10 peptide-like probes to select appropriate no npeptide actives from the MDDR database.