Identification of Novel Smyd1 Inhibitors for Cardiovascular Disease Treatment through Molecular Modelling

Smyd1 (SET And MYND Domain Containing 1) plays a crucial role in cardiomyocyte differentiation and cardiac morphogenesis, offering promising potential for the treatment of cardiovascular disease. However, the lack of human crystal structures and published inhibitors for Smyd1 has hindered progress in developing effective therapeutics. To address this gap, our study employs computational methods to identify novel Smyd1 inhibitors. We first generated a reliable human Smyd1 homology model and conducted an in-depth analysis of the compound binding modes within the Smyd family. Subsequently, we developed and executed a virtual screening pipeline, integrating pharmacophore screening, molecular docking, and molecular dynamics simulations, to search for potential hit compounds with inhibitory activity against Smyd1. Experimental testing of the 15 most promising compounds identified three novel compounds with promising inhibitor activity, comparable or even higher to that of Sinefungin, a ligand known to bind to the Smyd1 cofactor pocket. These findings provide valuable insights into the binding mode of Smyd1 hit compounds, suggesting their potential as lead candidates. In conclusion, we present a rational approach for the discovery of potential therapeutic agents, laying the foundation for future investigations into optimizing novel Smyd1 inhibitors.