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.

摘要

生态失调是个体疾病的主要原因，通常始于胃肠道。肠道，也称为第二大脑，在免疫信号传导中起主要作用。为了研究免疫级联，果蝇模型被认为针对位于中肠的 Imd 通路受体 (2F2L)。该受体进一步启动受细菌影响的免疫信号机制。为了抑制Imd途径，考虑了Imd与PDB的晶体结构：2F2L用于筛选合适的配体/抑制剂。根据我们之前的研究，筛选了来自香蕉植物的抗糖尿病配体的再利用，即羽扇豆醇 (LUP)、豆甾醇 (STI)、β-谷甾醇 (BST) 和伞形酮 (UMB)。这项研究确定了潜在的抑制剂以及气管毒素 (TCT)，微生物的主要肽聚糖成分。配合物2F2L-MLD、2F2L-CAP、2F2L-LUP、2F2L-BST、2F2L-STI和2F2L-UMB的分子对接和分子动力学模拟阐明了分子间相互作用对配体的抑制特性。本研究的结果推断 LUP 和 UMB 在筛选的候选者中是具有高稳定性和功能性的更好配体。这项研究提供了对植物衍生分子的生态失调及其改善的见解。已确定的药物（LUP 和 UMB）可能会作为微生物失调和其他相关发病机制（糖尿病和糖尿病神经病变）的抑制剂。此外，这项研究将拓宽苍蝇生物学研究的途径，并可用作快速的治疗模型，