Background: DNA methylation is considered a basic and longest-lasting mechanism of human genome organization. It is established during embryogenesis and lasts for the lifetime as the first step of epigenetic regulation. Dysregulation of DNA methylation causes apoptosis, aging, and various pathological conditions. The development of DNMT inhibitors is one of the greatest challenges for 21st-century pharmacology and biotechnology. DNA methyltransferases are a uniquely complex challenge considering the size and multiple complex regulatory mechanisms. Selective manipulation of DNA methylation in healthy tissues can be used to produce stem cells. In this study, we used a supercomputer to develop inhibitors and analyze the structure and function of the major human DNA methyltransferase DNMT1. Results: The binding site of the SAM cofactor in the active site of the enzyme is evolutionarily highly conserved, indicating that this part of the enzyme is described the best. 4WXX, 3PTA, and 4DA4 are three structural forms of DNMT1 from the PDB database that show different degrees of enzyme activity regulation and subtle differences in the active site. DNMT1 showed the highest mobility in its RFTS, CXXC, and BAH domains. Different enzyme forms have been used to screen compounds from commercial small molecule libraries to find compounds with the best binding affinity for the DNMT1 active site. The compounds were initially selected by the docking method. By that, compounds that exhibit shape-complementarity with the DNMT1 active site and generate the largest number of interactions were identified. The best-ranked compounds were used to describe the detailed binding mechanism by MD over 100 ns. Binding modes of identified compounds were compared to the binding of cofactor SAH as a reference ligand with a well-known binding mechanism. Conclusion: ELITE12 and MYB1 are two compounds from commercial compound libraries that do not show a significant improvement in stability and number of binding interactions relative to SAH. The development of small molecules with binding affinity to the DNMT1 active site depends on organic syntheses and specifically designed compounds.