Skeleton selectivity in complexation of chelerythrine and chelerythrine-like natural plant alkaloids with the G-quadruplex formed at the promoter of c-MYC oncogene: in silico exploration

'Pu27' is a G-rich 27 nucleotide sequence in the non-coding strand of the 'nuclear hypersensitive element (NHEIII1)', present in the promoter region of the c-MYC oncogene. Pu27 attains a stable secondary structure (G-quadruplex) and regulates the expression of c-MYC, thus stabilization of Pu27 using small molecules has become a novel strategy for developing cancer therapeutics. Recently the plant alkaloid chelerythrine has been explored as a probable anti-cancer agent with its novel mechanism of action i.e. stabilization of the G-quadruplex formed by Pu27. In the present study we have determined the binding characteristics of chelerythrine and three other chelerythrine-like plant alkaloids with the G-quadruplex formed by Pu27. Binding conformations of each ligand are obtained by molecular docking. Furthermore, the structural integrity of the built model and the conformational behavior of Pu27 upon binding of the ligands are established through all atom molecular dynamics simulations in an explicit solvent for 50 ns. Binding free energies of the ligands are estimated over the last 2 ns simulation run. We cultivated the gravity and influence of the position of methoxy group on the chelerythrine skeleton, tuning the binding pattern and energetics over its host, Pu27. Based on the results we categorized the ligands according to their better binding efficacy. Chelerythrine and the 12 methoxy analog of it showed the highest affinity towards complex formation. The in depth binding behaviors of these molecules were extracted from the conformational hyperspace of complexes reflected in their principal component analysis. We report the atomistic details of the binding patterns of chelerythrine and chelerythrine like molecules towards the G-quadruplex formed in Pu27. Chelerythrine and 12-methoxy chelerythrine show similar binding patterns, stacking over the 50 end of the sequence, methoxy substitution over the 12th position aids in the binding activity by enhancing the van der Waals energy contribution. A change in the position of methoxy groups over ring-A of chelerythrine alters the ligand binding.