G4-QuadScreen: A Computational Tool for Identifying Multi-Target-Directed Anticancer Leads against G-Quadruplex DNA

G-quadruplexes (G4s) are guanine-rich, four-stranded nucleic acid structures that are abundantly found in the promoter region of various oncogenes (cMYC, cKIT, KRAS, etc.) and in the telomeric region. The ligand-induced stabilization of G4s is shown to be efficient in targeted cancer therapy, and simultaneously targeting multiple G4s is beneficial. Thus, this study aimed to achieve the ‘stabilization of G4s with multi-target directed ligands (MTDL)’. We have developed different multi-tasking QSAR models to predict G4 interaction, G4 stabilization, G4 selectivity, and cytotoxicity and we have implemented them in the first computational tool, ‘G4-QuadScreen’, derived from this robust methodology with the functionality to screen-out a library of small-ligand molecules against G4 DNAs. A virtual screening using this ‘G4-QuadScreen’ server and a posterior experimental validation has allowed us to identify a total of three compounds with strong inhibitory effect on various human cancer cell lines, demonstrating the usefulness of computational tools to accelerate the discovery of novel anticancer therapies.