Promiscuous Ligands

Computational and experimental high-throughput screening are frequently used to discover new leads for drug design. Although novel ligands have been identified by these methods, it has become clear that screening hit lists are plagued by false positives. These nuisance compounds are ultimately found to be developmental dead-ends and are abandoned, often after considerable effort has been invested in them. Much work over the last decade has been devoted to exploring the origins of false-positive screening hits, and ligand promiscuity has emerged as one such cause. Well-known mechanisms of promiscuity include reactive species and privileged substructures. More recently, it has been found that some nonspecific screening hits form aggregates of 30–1000 nm in diameter. It has been proposed that these aggregate particles are responsible for the promiscuous behavior of many false positives and that aggregate-forming compounds may be widespread among screening hits. This chapter will review the known mechanisms of ligand promiscuity with an emphasis on the recently described model of aggregation. Experimental and computational methods for identifying promiscuous compounds will be described, and some outstanding questions in the field will be considered.