In Silico Optimization of the First DNA-Independent Mechanism-Based Inhibitor of Mammalian DNA Methyltransferase DNMT1, Epi-Informatics, (2016), doi.org/10.1016/B978-0-12-802808-7.00005-8
Abstract: Inhibitors of DNA methylation can be used to control functional organization of human genome in basic research and regenerative medicine. We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel mechanism-based suicide-inhibitors of mammalian DNA methyltransferase DNMT1. The inhibitors are designed to act as transition state analogs that can bind simultaneously to the cofactor binding site and the active site on DNMT1. The two binding sites and the mechanism-based suicide-inhibition are combined to provide highly potent and highly specific inhibition. The stability of presented DNMT1-inhibitor complex is described in detail using 58 modifications that affect flexibility and binding interactions at specific sites within the complex. Presented results can guide synthesis and optimization of some highly specific mechanism-based inhibitors of mammalian DNA methylation with specific pharmacological properties.