Protein promiscuity in drug discovery, drug-repurposing and antibiotic resistance.

Proteins are supposed to bind to their substrates/ligands in a specific manner via their pre-formed binding sites, according to classical biochemistry. In recent years, several types of deviations from this norm have been observed and called promiscuous behavior. Enzymatic promiscuities allow several biochemical functions to be carried out by the same enzyme. The promiscuous activity can also be the origin of "new proteins" via gene duplication. In more recent years, proteins from prokaryotes, eukaryotes and viruses have been found to have intrinsic disorder and lack a preformed binding site. Intrinsic disorder is exploited in regulatory proteins such as those that are involved in transcription and signal transduction. Such proteins function by folding locally while binding to their ligands or interacting with other proteins. These phenomena have also been classified as examples of protein promiscuity and encompass diverse kinds of ligands that can bind to a protein. Given the significant extent of structural homology in many protein families, it is not surprising that ligands also have been found to display promiscuity. Promiscuous behavior of proteins offers both challenges and opportunities to the drug discovery programs such as drug repurposing. Pathogens when exposed to antibiotics exploit protein promiscuity in several ways to develop resistance to the drug. There is increasing evidence now to support that the disorder in proteins is a major tool used by pathogens for virulence and evade drug action by exploiting protein promiscuity. This review provides a holistic view of this multi-faceted phenomenon called protein promiscuity.