Discovery of novel CDK4/6 inhibitors from fungal secondary metabolites.

The development of targeted therapies for breast cancer, particularly those focusing on cyclin-dependent kinases 4/6 (CDK4/6), has significantly improved patient outcomes. However, the currently approved CDK4/6 inhibitors are associated with various side effects, underscoring the need for novel compounds with enhanced efficacy and safety profiles. This study aimed to identify potential CDK4/6 inhibitors from MeFSAT, a database of fungal secondary metabolites using an in-silico screening approach. The virtual screening process incorporated drug-likeness filters, ADME and toxicity predictions, consensus molecular docking, and 200 ns molecular dynamics simulations. Out of 411 initial compounds, two molecules demonstrated favorable binding interactions and stability with the CDK4/6 protein complex. The MTT assay showed that MSID000025 had dose-dependent cytotoxicity against MCF7 breast cancer cells. This suggests that MSID000025 could be a good candidate CDK4/6 inhibitor for treating breast cancer. Our study highlights the potential of fungal secondary metabolites as a source of novel compounds for drug discovery. It provides a framework for identifying CDK4/6 inhibitors with improved therapeutic properties.