Modeling the Structures of Ternary Complexes Mediated by Molecular Glues

The term “molecular glue” (abbreviated hereafter as MG) was first coined in 1992 by Stuart Schreiber to describe how the macrocyclic natural products cyclosporin A, rapamycin, and FK506 induce the formation of ternary complexes (i.e. complexes made from three components). In this chapter, the authors describe the extension of the PROTAC modeling techniques to predict the structure of ternary complexes mediated by MGs. Two distinct approaches are detailed. The first approach treats MGs as they are commonly conceptualized – as whole, indivisible molecules, placed via small molecule docking at protein–protein interfaces (PPIs), which are themselves predicted by protein–protein docking. The second approach instead treats MGs as “linkerless PROTACs,” i.e. as molecules that, despite their nominal monovalency, can be partitioned into two binding parts, each of which can be viewed as primarily interacting with just one of the proteins in the ternary complex.