Speaker
Description
c-Myc is a key transcription factor involved in regulating cell growth and proliferation; however, its intrinsically disordered structure has made it a challenging target for traditional drug discovery. Effective transcriptional activity requires dimerization with MAX, enabling it to bind DNA and regulate gene expression. However, the disordered nature of its N-terminal transactivation domain (TAD) limits the formation of stable binding sites, complicating the development of direct inhibitors. Small molecules, such as 10074-G5, have shown promise in binding to this flexible, disordered region and inhibiting c-Myc activity. To investigate this interaction, we employed a 1000-nanosecond molecular dynamics (MD) simulation to study the binding behavior of 10074-G5 with the disordered transactivation domain of c-Myc using GROMACS, focusing on structural stability (RMSD), compactness (Rg), radial distribution function (RDF), residue-level flexibility (RMSF), hydrogen bond interactions, and binding affinity through free energy calculations.
Our findings revealed that 10074-G5 formed stable and persistent interactions with c-Myc, stabilizing key residues within the flexible region. RMSD and Rg analyses indicated a transition toward a more compact and ordered conformation upon ligand binding, RDF analysis indicated preferential and stable proximity between the ligand and specific residues of the protein, RMSF analysis showed reduced fluctuations in key binding regions, suggesting localized stabilization of the protein structure, hydrogen bond analysis revealed consistent bonding throughout the simulation, while free energy calculations confirmed favorable binding energy.
These findings highlight the potential of 10074-G5 as a lead compound for therapeutically targeting c-Myc, demonstrate the utility of MD simulations in studying intrinsically disordered proteins, and provide a framework for the rational design of effective c-Myc inhibitors.
Keywords: Molecular Dynamics (MD), GROMACS, c-Myc inhibitors, Protein Stabilization, Binding Free Energy.