Speaker
Description
About 70% of human cancer is driven by the heterodimerization of c-Myc oncoprotein and its obligate partner, Max. Despite the fact that c-Myc is involved in vital cellular processes such as cell cycle progression, apoptosis, cell differentiation and metabolism, it exerts its oncogenic functions when it complexes with Max, enabling DNA binding and gene activation. While several small molecular weight compounds such as 4-(2-(furan-2-yl)-6-(4-nitrophenyl) pyridin-4-yl) benzamide (Kj-Pyr-9) have proven to inhibit and/or disrupt the heterodimerization process, the precise molecular interaction and binding sites involved remain uncertain. In this studies, molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding behavior of Kj-Pyr-9 with c-Myc. By blind docking c-Myc with Kj-Pyr-9, some key residues involved in the ligand stabilization include PRO191, PHE195, LEU199, TYR197 on the c-Myc protein interacting with carbon (4, 6, 8-14,17,21-23,25,26) and Nitrogen7 on the Kj-Pyr-9 ligand. By site-specific docking of Kj-Pyr-9 with c-Myc at known heterodimerization sites or pockets with Max as reported in literature, (Arg 299, Arg 424, Leu 420 and Ile 403), analyses of Ile403 reveals consistent hydrophobic and pi-pi stacking interactions with the residues at the helix-loop-helix leucine zipper domain and hydrophilic interactions at Leu 420 providing insights into the stability and specificity. These findings advance our understanding of how small molecules interact with c-Myc to disrupt the heterodimerization with max. Ultimately, this work contributes to efforts aimed at targeting the undruggable cancer driver – c-Myc.
Keywords: Kj-pyr-9, c-Myc, Cancer, Target, Heterodimerization, Oncogene