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

Abstract

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.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Immunity
• Imd
• simulation
• in silico
• dynamics
• lifestyle disorder
• diabetes
• diabetic neuropathy

Acknowledgements

FZ thank Prof. Dr. Shubha Gopal, Department of Studies in Microbiology, the University of Mysore for her mentorship. Special thanks to Dr. MN Nagendra Prasad, Dr. Ramith Ramu and Ms. Aishwarya T. Devi, JSS University Research Foundation, SJCE Campus, Mysuru, for their long-term collaboration in phytochemistry and fly research. Sincere gratitude to Dr. Sinosh Skariyachan, Department of Microbiology, St. Pius X College Rajapuram, Kasaragod, Kerala, and Dr. Shukath Ara Khanum, Department of Chemistry, Yuvaraj College, Mysuru. Mr. PS would like to thank DST-KSTePS, GoK, for providing DST-Ph.D fellowship (LIF-09-2018-19), and Mr. Anirudh Gururaj Patil (LIF-02-2019-20) and Ms. Aishwarya S. for their technical support during the design and execution of the study. All the authors thank Siddaganga Institute of Technology, Tumakuru – 572 103 and Karnataka Biotechnology and Information Technology Services (KBITS), Bangalore, for providing the grant to establish the computational facility under Biotech Policy-II, Biotechnology Finishing School, Biotechnology Skill Enhancement Programme (BiSEP) at the Department of Biotechnology at SIT, Karnataka. All the authors thank Mr. Vimal John Samuel, Mrs. K.B. Premakumari, Mr. Sunil and Prof. Dr. V. Murgan, from the School of Pharmacy, DSU, for their technical assistance during the preparation of the manuscript. Further, we extend our gratitude towards the management and office bearers of Dayananda Sagar University, Bengaluru – 560 111, Karnataka, India, for constant inspiration, motivation, and encouragement to pursue and implement the current research work.

Disclosure statement

All authors declare no conflict of interest.