  Protein-protein interactions are the basis of many important physiological
processes and are currently promising, yet difficult, targets for drug
discovery. In this context, inhibitor of apoptosis proteins (IAPs)-mediated
interactions are pivotal for cancer cell survival; the interaction of the BIR1
domain of cIAP2 with TRAF2 was shown to lead the recruitment of cIAPs to the
TNF receptor, promoting the activation of the NF-\kappa B survival pathway. In
this work, using a combined in silico-in vitro approach, we identified a
drug-like molecule, NF023, able to disrupt cIAP2 interaction with TRAF2. We
demonstrated in vitro its ability to interfere with the assembly of the
cIAP2-BIR1/TRAF2 complex and performed a thorough characterization of the
compound's mode of action through 248 parallel unbiased molecular dynamics
simulations of 300 ns (totaling almost 75 {\mu}s of all-atom sampling), which
identified multiple binding modes to the BIR1 domain of cIAP2 via clustering
and ensemble docking. NF023 is, thus, a promising protein-protein interaction
disruptor, representing a starting point to develop modulators of NF-\kappa
B-mediated cell survival in cancer. This study represents a model procedure
that shows the use of large-scale molecular dynamics methods to typify
promiscuous interactors.
