Computational discovery of novel inhibitory candidates targeting versatile transcriptional repressor MBD2.

Genome methylation is a key epigenetic mechanism in various biological events such as development, cellular differentiation, cancer progression, aging, and iPSC reprogramming. Crosstalk between DNA methylation and gene expression is mediated by MBD2, known as the reader of DNA methylation and suggested as a drug target. Despite its magnitude of significance, a scarcely limited number of small molecules to be used as inhibitors have been detected so far. Therefore, we screened a comprehensive compound library to elicit MBD2 inhibitor candidates. Promising molecules were subjected to computational docking analysis by targeting the methylated DNA-binding domain of human MBD2. We could detect reasonable binding energies and docking residues, presumably located in druggable pockets. Docking results were also validated via MD simulation and per-residue energy decomposition calculation. Drug-likeness of these small molecules was assessed through ADMET prediction to foresee off-target side effects for future studies. All computational approaches notably highlighted two compounds named CID3100583 and 8,8-ethylenebistheophylline. These compounds have become prominent as novel candidates, possibly disrupting MBD2-DNA interaction. Consequently, these compounds have been considered prospective inhibitors with the usage potential in a wide range of applications from cancer treatment to somatic cell reprogramming protocols.