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Published on: November 11, 2016
Computational and Experimental Characterization of NF023, A Candidate Anticancer Compound Inhibiting cIAP2/TRAF2
Federica Cossu1,2, Luca Sorrentino1,2, Elisa Fagnani1
1Istituto di Biofisica, Consiglio Nazionale Delle Ricerche (CNR-IBF), Via Celoria, 26, I-20133 Milan, Italy.
Abstract:
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.
Insights
Researchers identified NF023, a molecule that disrupts protein-protein interactions crucial for cancer cell survival. This discovery offers a new strategy for developing cancer therapies targeting the NF-κB pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Protein-protein interactions (PPIs) are fundamental to physiological processes and represent challenging drug targets.
- Inhibitor of apoptosis proteins (IAPs)-mediated interactions are critical for cancer cell survival.
- The interaction between cIAP2's BIR1 domain and TRAF2 recruits cIAPs to the TNF receptor, activating the NF-κB survival pathway.
Purpose of the Study:
- To identify a molecule capable of disrupting the cIAP2-BIR1/TRAF2 interaction.
- To characterize the mechanism of action of the identified molecule.
- To establish a model procedure for using large-scale molecular dynamics to study PPI disruptors.
Main Methods:
- Combined in silico and in vitro approaches for molecule identification.
- In vitro assays to confirm interference with complex assembly.
- Extensive molecular dynamics (MD) simulations (248 parallel, 300 ns each) for mode of action characterization.
- Clustering and ensemble docking for binding mode analysis.
Main Results:
- Identification of the drug-like molecule NF023.
- In vitro validation of NF023's ability to disrupt the cIAP2-BIR1/TRAF2 complex.
- Detailed characterization of NF023's multiple binding modes to the cIAP2 BIR1 domain using MD simulations.
- Demonstration of NF023 as a protein-protein interaction disruptor.
Conclusions:
- NF023 is a promising disruptor of cIAP2-TRAF2 interaction.
- NF023 serves as a starting point for developing modulators of NF-κB-mediated cancer cell survival.
- Large-scale MD simulations are effective for characterizing promiscuous protein interactors.
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