Discovery of novel CDK4/6 inhibitors from fungal secondary metabolites

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Targeted therapies, especially cyclin-dependent kinases 4/6 (CDK4/6) inhibitors, have advanced breast cancer treatment.
• Existing CDK4/6 inhibitors present side effects, necessitating the search for novel agents with better safety and efficacy.
• Fungal secondary metabolites represent an underexplored reservoir for potential therapeutic compounds.

Purpose of the Study:

• To identify novel CDK4/6 inhibitors from the MeFSAT fungal metabolite database using in-silico methods.
• To evaluate the drug-likeness, ADME/toxicity, binding affinity, and stability of potential inhibitors.
• To validate the anti-cancer activity of promising candidates against breast cancer cell lines.

Main Methods:

• In-silico screening of the MeFSAT database for potential CDK4/6 inhibitors.
• Application of drug-likeness filters, ADME/toxicity predictions, and molecular docking.
• Conducting 200 ns molecular dynamics simulations to assess binding stability.
• In-vitro cytotoxicity evaluation using MTT assay on MCF7 breast cancer cells.

Main Results:

• Two compounds exhibited favorable binding interactions and stability with the CDK4/6 protein complex after virtual screening of 411 initial molecules.
• The compound MSID000025 demonstrated dose-dependent cytotoxicity against MCF7 breast cancer cells.
• The study identified MSID000025 as a potential candidate for a novel CDK4/6 inhibitor.

Conclusions:

• Fungal secondary metabolites are a valuable source for discovering novel therapeutic agents.
• MSID000025 shows promise as a potential CDK4/6 inhibitor for breast cancer treatment.
• The in-silico framework employed can guide the identification of improved CDK4/6 inhibitors.