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

Colorectal cancer (CRC), especially metastatic (mCRC) form, becomes a major reason behind cancer morbidity worldwide, whereas the treatment strategy is not optimum. Several novel targets are under investigation for mCRC including the autophagy pathway. Natural compounds including dietary lignans are sparsely reported as autophagy modulators. Nonetheless, the interaction between dietary lignans and core autophagy complexes are yet to be characterised. We aimed to describe the interaction between the dietary lignans from flaxseed (Linum usitatissimum) and sesame seeds (Sesamum indicum) along with the enterolignans (enterodiol and enterolactone) and the UNC-51-like kinase 1 and 2 (ULK1/2), important kinases required for the autophagy. A range of in-silico technologies viz. molecular docking, drug likeness, and ADME/T was employed to select the best fit modulator and/or inhibitor of the target kinases from the list of selected lignans. Drug likeness and ADME/T studied further selected the best-suited lignans as potential autophagy inhibitor. Molecular dynamic simulation (MDS) analyses were used to validate the molecular docking results. Binding free energies of the protein-ligand interactions by MM-PBSA method further confirmed best-selected lignans as ULK1 and/or ULK2 inhibitor. In conclusion, three dietary lignans pinoresinol, medioresinol, and lariciresinol successfully identified as dual ULK1/2 inhibitor/modifier, whereas enterodiol emerged as a selective ULK2 inhibitor/modifier.