Targeting Imd pathway receptor in and repurposing of phyto-inhibitors: structural modulation and molecular dynamics.

Dysbiosis is a major cause of disease in an individual, generally initiated in the gastrointestinal tract. The gut, also known as the second brain, constitutes a major role in immune signaling. To study the immunity cascade, the Drosophila model was considered targeting the Imd pathway receptor (2F2L) located in the midgut. This receptor further initiates the immune signaling mechanism influenced by bacteria. To inhibit the Imd pathway, the crystal structure of Imd with PDB: 2F2L was considered for the screening of suitable ligand/inhibitor. In light of our previous studies, repurposing of anti-diabetic ligands from the banana plant namely lupeol (LUP), stigmasterol (STI), β-sitosterol (BST) and umbelliferone (UMB) were screened. This study identifies the potential inhibitor along with the tracheal toxin (TCT), a major peptidoglycan constituent of microbes. The molecular docking and molecular dynamics simulation of complexes 2F2L-MLD, 2F2L- CAP, 2F2L-LUP, 2F2L-BST, 2F2L-STI and 2F2L-UMB elucidates the intermolecular interaction into the inhibitory property of ligands. The results of this study infer LUP and UMB as better ligands with high stability and functionality among the screened candidates. This study provides insights into the dysbiosis and its amelioration by plant-derived molecules. The identified drugs (LUP & UMB) will probably act as an inhibitor against microbial dysbiosis and other related pathogenesis (diabetes and diabetic neuropathy). Further, this study will widen avenues in fly biology research and which could be used as a therapeutic model in the rapid, reliable and reproducible screening of phytobiologics in complementary and alternative medicine for various lifestyle associated complications.