Computed interactions of berenil with restricted foldamers of c-MYC DNA G-quadruplexes.

G-quadruplexes (G4s) are secondary four-stranded DNA helical structures made up of guanine-rich nucleic acids that can assemble in the promoter regions of multiple genes under the appropriate conditions. Stabilization of G4 structures by small molecules can regulate transcription in non-telomeric regions, including in proto-oncogenes and promoter regions, contributing to anti-proliferative and anti-tumor activities. Because G4s are detectable in cancer cells but not in normal cells, they make excellent drug discovery targets. Diminazene, DMZ (or berenil), has been shown to be an efficient G-quadruplex binder. Due to the stability of the folding topology, G-quadruplex structures are frequently found in the promotor regions of oncogenes and may play a regulatory role in gene activation. Using molecular docking and molecular dynamics simulations on several different binding poses, we have studied DMZ binding toward multiple G4 topologies of the c-MYC G-quadruplex. DMZ binds preferentially to G4s that have extended loops and flanking bases. This preference arises from its interactions with the loops and the flanking nucleotides, which were not found in the structure lacking extended regions. The binding to the G4s with no extended regions instead occurred mostly through end stacking. All binding sites for DMZ were confirmed by 100 ns molecular dynamics simulations and through binding enthalpies calculated using the MM-PBSA method. The primary driving forces were electrostatic, as the cationic DMZ interacts with the anionic phosphate backbone, and through van der Waals interactions, which primarily contributed in end stacking interactions.Communicated by Ramaswamy H. Sarma.