Protein–protein interactions (PPIs) are essential
for biological
processes including immune reactions and diseases. Inhibition of PPIs
by drug-like compounds is a common basis for therapeutic approaches.
In many cases the flat interface of PP complexes prevents discovery
of specific compound binding to cavities on one partner and PPI inhibition.
However, frequently new pockets are formed at the PP interface that
allow accommodation of stabilizers which is often as desirable as
inhibition but a much less explored alternative strategy. Herein,
we employ molecular dynamics simulations and pocket detection to investigate
18 known stabilizers and associated PP complexes. For most cases,
we find that a dual-binding mechanism, a similar stabilizer interaction
strength with each protein partner, is an important prerequisite for
effective stabilization. A few stabilizers follow an allosteric mechanism
by stabilizing the protein bound structure and/or increase the PPI
indirectly. On 226 protein–protein complexes, we find in >75%
of the cases interface cavities suitable for binding of drug-like
compounds. We propose a computational compound identification workflow
that exploits new PP interface cavities and optimizes the dual-binding
mechanism and apply it to 5 PP complexes. Our study demonstrates a
great potential forin silicoPPI stabilizers discovery
with a wide range of therapeutic applications.