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Protein-protein interactions are the basis of many important physiologicalprocesses and are currently promising, yet difficult, targets for drugdiscovery. In this context, inhibitor of apoptosis proteins (IAPs)-mediatedinteractions are pivotal for cancer cell survival; the interaction of the BIR1domain of cIAP2 with TRAF2 was shown to lead the recruitment of cIAPs to theTNF receptor, promoting the activation of the NF-\kappa B survival pathway. Inthis work, using a combined in silico-in vitro approach, we identified adrug-like molecule, NF023, able to disrupt cIAP2 interaction with TRAF2. Wedemonstrated in vitro its ability to interfere with the assembly of thecIAP2-BIR1/TRAF2 complex and performed a thorough characterization of thecompound's mode of action through 248 parallel unbiased molecular dynamicssimulations of 300 ns (totaling almost 75 {\mu}s of all-atom sampling), whichidentified multiple binding modes to the BIR1 domain of cIAP2 via clusteringand ensemble docking. NF023 is, thus, a promising protein-protein interactiondisruptor, representing a starting point to develop modulators of NF-\kappaB-mediated cell survival in cancer. This study represents a model procedurethat shows the use of large-scale molecular dynamics methods to typifypromiscuous interactors.

Computational and Experimental Characterization of NF023, A Candidate Anticancer Compound Inhibiting cIAP2/TRAF2 Assembly