Leveraging Flavonoids as Potential Inhibitors of METTL3 in Combating Cancer: A Combined Structure‐Based Drug Design and DFT Approach

Abstract Methyltransferase‐like 3 (METTL3) serves as a primary catalytic enzyme within the N6‐ methyladenosine (m6 A) methyltransferase system, playing a crucial role in various biological processes. However, its involvement in the pathogenesis of several cancers, have been well documented. The pursuit of small molecule inhibitors to counteract the cancer‐promoting effects of METTL3 has gained considerable momentum; however, no approved drugs are available. In this study, we employed computational techniques, including structure‐based virtual screening, consensus molecular docking, Density Function Theory calculations and MMPBSA energy profiling to identify potential METTL3 inhibitors from flavonoids. ST024026, ST99039 and ST4135876 were identified as promising candidates for METTL3 inhibition, as indicated by their favorable docking scores and robust energy profiles. Notably, their binding interactions were characterized by strong hydrogen bonds and hydrophobic contacts, ensuring high stability within the METTL3 binding site. Furthermore, these compounds exhibited favorable physicochemical properties and ADME characteristics, coupled with minimal toxicity. Notably, their binding induced conformational changes in the protein, underscoring their potential as METLL3 inhibitors. These findings highlight the selected flavonoids as potential novel entry inhibitors subject to modifications and optimizations. To advance this line of research, additional biochemical testing and experimental validation are warranted to facilitate the development of highly selective and effective METTL3 inhibitors.