Identifying and characterizing promiscuous targets: Implications for virtual screening

Introduction: Ligand-based shape matching approaches have become established as important and popular virtual screening (VS) techniques. However, despite their relative success, the question of how to best choose the initial query compounds and their conformations remains largely unsolved. This issue gains importance when dealing with promiscuous targets, that is, proteins that bind multiple ligand scaffold families in one or more binding site. Conventional shape matching VS approaches assume that there is only one binding mode for a given protein target. This may be true for some targets, but it is certainly not true in all cases. Several recent studies have shown that some protein targets bind to different ligands in different ways. Areas covered: The authors discuss the concept of promiscuity in the context of virtual drug screening, and present and analyze several examples of promiscuous targets. The article also reports on the impact of the query conformation on the performance of shape-based VS and the potential to improve VS performance by using consensus shape clustering techniques. Expert opinion: The notion of polypharmacology is becoming highly relevant in drug discovery. Understanding and exploiting promiscuity present challenges and opportunities for drug discovery endeavors. The examples of promiscuity presented here suggest that promiscuous targets and ligands are much more common than previously assumed, and this should be taken into account in practical VS protocols. Although some progress has been made, there is a need to develop more sophisticated computational techniques and protocols that can identify and characterize promiscuous targets on a genomic scale.