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

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-κB 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 μs 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-κB-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.