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Updated: Jul 8, 2025
Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
Structure-guided screening of protein-protein interaction for the identification of Myc-Max heterodimer complex
Shovonlal Bhowmick1, Kunal Roy2, Achintya Saha1
1Department of Chemical Technology, University of Calcutta, Kolkata, India.
Abstract:
De-regulation of oncogenic myelocytomatosis (c-Myc or Myc) transcription factor is one of the most common molecular anomalies encountered in human cancers, and it is typically linked to many aggressive malignancies including breast, lung, cervix, colon glioblastomas, and other haematological organs. The Myc belongs to the basic helix-loop-helix zipper protein family (bHLH-ZIP), and its dimerization with another principal interactor protein partner Myc-associated factor X (Max) is essentially required for cellular transformation, cell growth and proliferation, and transcriptional activation. Intermolecular interactions have been evaluated between hetero-dimer Myc-Max protein, which identified protein-protein interaction (PPI) specific modulators using highly précised molecular docking study followed by long-range interaction stability analyzed through molecular dynamic (MD) simulation. Moreover, ADME profile analyses have been estimated for screened hit compounds. MM-GBSA-based binding free energy (ΔG) estimations have been performed for all screened hit compounds obtained from multi-step molecular docking-based virtual screening technique. According to the employed various rigorous multi-chemometric techniques, four identified inhibitors/modulators appear to have a considerable number of intermolecular contacts with hotspot residues in the hetero-dimer interface region of the Myc-Max PPI complex. However, identified hit compounds might need further structural optimization or extensive biophysical analyses for better understanding of the molecular mechanism for exhibiting the Myc-Max PPI interface binding stability.
Insights
Dysregulated c-Myc (myelocytomatosis oncogene) drives aggressive cancers. This study identified four novel inhibitors targeting the Myc-Max protein-protein interaction (PPI) complex, offering potential therapeutic avenues.
Area of Science:
- Computational chemistry and molecular modeling
- Cancer biology and molecular oncology
- Drug discovery and medicinal chemistry
Background:
- The oncogenic transcription factor c-Myc (myelocytomatosis oncogene) is frequently deregulated in aggressive human cancers.
- c-Myc function relies on dimerization with Max, forming a complex essential for cell growth and proliferation.
- Targeting the Myc-Max protein-protein interaction (PPI) presents a promising strategy for cancer therapy.
Purpose of the Study:
- To identify specific modulators of the Myc-Max hetero-dimer PPI complex.
- To evaluate the binding stability and potential therapeutic efficacy of identified compounds.
Main Methods:
- Multi-step molecular docking and virtual screening to identify potential inhibitors.
- Molecular dynamics (MD) simulations to analyze long-range interaction stability.
- MM-GBSA calculations for binding free energy estimation and ADME profiling.
Main Results:
- Four compounds demonstrated significant intermolecular contacts with hotspot residues at the Myc-Max PPI interface.
- Molecular dynamics simulations confirmed the stability of interactions for the identified hit compounds.
- Binding free energy calculations supported the inhibitory potential of the screened compounds.
Conclusions:
- The study successfully identified four potential modulators of the Myc-Max PPI complex using computational approaches.
- These identified compounds warrant further structural optimization and biophysical validation for therapeutic development.
- Targeting the Myc-Max interaction offers a viable strategy against cancers driven by c-Myc deregulation.
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