Targeting UNC-51-like kinase 1 and 2 by lignans to modulate autophagy: possible implications in metastatic colorectal cancer

Area of Science:

• Molecular biology and oncology
• Natural product chemistry
• Computational drug discovery

Background:

• Metastatic colorectal cancer (mCRC) poses a significant global health challenge with suboptimal treatment outcomes.
• The autophagy pathway is an emerging therapeutic target for mCRC.
• Dietary lignans, natural compounds found in flax and sesame seeds, have shown limited investigation as autophagy modulators.

Purpose of the Study:

• To characterize the interaction between dietary lignans (from flaxseed and sesame seeds) and core autophagy kinases, specifically UNC-51-like kinase 1 and 2 (ULK1/2).
• To identify potential autophagy inhibitors or modulators among dietary lignans for mCRC treatment.

Main Methods:

• In-silico techniques including molecular docking, drug likeness, and ADME/T prediction were employed.
• Molecular dynamic simulations (MDS) were used to validate docking results.
• MM-PBSA calculations determined binding free energies for protein-ligand interactions.

Main Results:

• Three dietary lignans—pinoresinol, medioresinol, and lariciresinol—were identified as dual inhibitors/modifiers of ULK1 and ULK2.
• Enterodiol was identified as a selective ULK2 inhibitor/modifier.
• Computational analyses confirmed the binding affinity and potential inhibitory roles of these lignans.

Conclusions:

• Specific dietary lignans possess the potential to modulate the autophagy pathway by targeting ULK1/2 kinases.
• These findings suggest a novel therapeutic strategy for mCRC involving natural compounds.
• Further research into lignan-based autophagy modulation could lead to improved mCRC treatment options.