An industrial perspective on positive allosteric modulation as a means to discover safe and selective drugs

Positive allosteric modulation is an innovative strategy for the discovery of drugs acting at 7-transmembrane receptors. Screening has led to the identification of numerous starting points for medicinal chemistry typified by novel mechanisms of action. The progression of compounds through hit-to-candidate phases and pre-clinical animal models, however, proves very challenging. In this review, we discuss advances in the area and interrogate the mechanistic profiling required to support drug discovery programs and fully exploit the therapeutic potential of positive allosteric modulators.