The time-consuming and work-intensive determination of high-resolution G4-ligand structures is often a formidable task. Structure-activity relationships can guide rational drug development and help identify promising candidates however, the immense chemical space of possible ligands cannot be fully explored despite the availability of high-throughput screening methods. Alternatively, the MycG4 is a promising anticancer drug target because of its function as transcription silencer and is one of the most studied G4s for small molecule targeting. The MYC protein is an important transcription factor that is commonly deregulated in human cancers however, it is often considered ‘undruggable’. A prominent example and model structure for parallel G4s with short loops is the major G4 formed in the promoter region of the MYC oncogene, MycG4 ( Figure 1a). Parallel G4s are prevalent in the human genome, such as promoter DNA G4s and RNA G4s. In parallel G4s, the 5′- and 3′-terminal flanking regions mostly form capping structures over the external G-tetrads, whereas in non-parallel G4s, the loop regions are also involved in capping structure formation. G4s can be classed as parallel and non-parallel structures depending on the directionality of the involved G-runs, which are connected by loop sequences. The study shows that current docking programs should be used with caution to predict G4 DNA-small molecule binding modes. We found that docking accuracy is mainly limited by the scoring functions. The results indicate that there are considerable differences in the performance of the docking programs and that DOCK 6 with GB/SA rescoring performs better than the other programs. Here we perform the first systematic evaluation of four commonly used docking programs (AutoDock Vina, DOCK 6, Glide, and RxDock) for G4 DNA-ligand binding pose prediction using four small molecules whose complex structures with the MycG4 have been experimentally determined in solution. However, DNA, and in particular G4, binding sites differ significantly from protein targets. Molecular docking has become an essential tool in structure-based drug discovery for protein targets, and is also increasingly applied to G4 DNA. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are prevalent in promoter DNA G4s and RNA G4s. G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target.
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