The structural basis of drugs targeting protein-protein interactions uncovered with the protein-ligand interaction profiler PLIP

Abstract

Promiscuity of drugs and targets plays an important role in drug-target prediction, ranging from the explanation of side effects to their exploitation in drug repositioning. A specific form of promiscuity concerns drugs, which interfere with protein-protein interactions. With the rising importance of such drugs in drug discovery and with the large-scale availability of structural data, the question arises on the structural basis of this form of promiscuity and the commonalities of the underlying protein-ligand (PLI) and protein-protein interactions (PPI). To this end, we employ the protein-ligand interaction profiler, PLIP, to characterize the PLI and PPI of MDM2/p53, Bcl-2/BAX, XIAP/Casp9, CCR5/gp120, and BRD/H4. We show that the wealth of existing complexes in PDB, of predicted protein structures, and of molecular docking results gives deep insights into the design principles for drugs targeting protein interactions. Drugs targeting protein interaction interfaces are a promising avenue in drug discovery. Understanding drug and target promiscuity at a structural level will pave the way to deliver on this promise.