Inhibition of cMYC-MAX transcription factors hetero-dimerization with structurally engineered omoMYC to downregulate oncogenic pathways in renal carcinoma

In the current study, we employed, structural informatics, and molecular simulation-based methods to engineer OmoMyc, a c-Myc dominant negative protein, to design novel mutants that could abrogate the c-MYC-MAX complex in Renal Carcinoma (RC). Among the total 472 mutations, only six mutations A61Q, Q64E, Q64K, N77R, Q64E-N77R, and Q64K-N77R were reported to increase the binding affinity and subjected to subsequent analysis such as protein-protein docking. The docking results revealed that the predicted mutants improve the func-tionality of the OmoMyc by not only increasing the binding affinity but also vdW and electrostatic energy in each complex that consequently increase the binding of the engineered OmoMyc by establishing extra hydrogen bonds, salt-bridges, and non-bonded contacts. Molecular simulation revealed a more stable behavior by the mutant complexes in contrast to the native OmoMyc however structural perturbations were reported in the regions, DBD (DNA-binding domain), loop region, and minor deviations at CTD (C terminal domain). Moreover, the hydrogen bonding and binding free energy results further validated the promising activity of our predicted mutants of OmoMyc. The results for TBE (total binding energy) revealed that the for each complex the TBE was calculated to be-87.88 & PLUSMN; 0.16 kcal/mol (WT OmoMyc-MAX),-91.89 & PLUSMN; 0.21 kcal/mol (A61Q OmoMyc-MAX),-91.55 & PLUSMN; 0.20 kcal/mol (Q64E OmoMyc-MAX),-95.17 & PLUSMN; 0.24 kcal/mol (Q64K OmoMyc-MAX),-96.49 & PLUSMN; 0.22 kcal/mol (N77R OmoMyc-MAX),-97.76 & PLUSMN; 0.22 kcal/mol (Q64E-N77R OmoMyc-MAX), and-95.31 & PLUSMN; 0.20 kcal/mol (Q64K-N77R OmoMyc-MAX) respectively. The results for TBE revealed promising results that allow the mutants to competitively inhibit the c-Myc-MAX complex more swiftly. Additionally, the internal motion and energy landscape were altered. These findings provide important insights into the potential of the mutants of OmoMyc as a therapeutic candidate for cancer treatment, particularly renal carcinoma, and could pave the way for the development of more effective clinical versions of OmoMyc.