Computational and Experimental Characterization of NF023, A Candidate Anticancer Compound Inhibiting cIAP2/TRAF2 Assembly
datasetposted on 04.09.2020, 18:34 by Federica Cossu, Luca Sorrentino, Elisa Fagnani, Mattia Zaffaroni, Mario Milani, Toni Giorgino, Eloise Mastrangelo
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.