Role of protein-protein interactions in allosteric drug design for DNA methyltransferases

DNA methyltransferases (DNMTs) not only play key roles in epigenetic gene regulation, but also serve as emerging targets for several diseases, especially for cancers. Due to the multi-domains of DNMT structures, targeting allosteric sites of protein-protein interactions (PPIs) is becoming an attractive strategy in epigenetic drug discovery. This chapter aims to review the major contemporary approaches utilized for the drug discovery based on PPIs in different dimensions, from the enumeration of allosteric mechanism to the identification of allosteric pockets. These include the construction of protein structure networks (PSNs) based on molecular dynamics (MD) simulations, performing elastic network models (ENMs) and perturbation response scanning (PRS) calculation, the sequence-based conservation and coupling analysis, and the allosteric pockets identification. Furthermore, we complement this methodology by highlighting the role of computational approaches in promising practical applications for the computer-aided drug design, with special focus on two DNMTs, namely, DNMT1 and DNMT3A.