Department of Bioinformatics, Cancer Informatics Laboratory, Alagappa University, Science Campus, Karaikudi, Tamil Nadu, India.
Department of Biotechnology and Bioinformatics, Bishop Heber College (Autonomous), Tennur, Tiruchirappalli Tamil Nadu, India.
Curr Drug Metab. 2022;23(4):299-316. doi: 10.2174/1389200223666220511162234.
Drosophila melanogaster is a prominent organism in developmental biology research and in studies related to pathophysiological conditions like cancer and Alzheimer's disease. The fruit fly gut contains several cytochrome P450s (CYP450s), which have central roles in Drosophila development and in the normal physiology of the gut. Since the crystal structures of these proteins have not been deciphered yet, we modeled the structure of 29 different D. melanogaster gut CYP450s using Prime (Schrödinger). The sequences of chosen D. melanogaster gut CYP450s were compared with that of their human counterparts. The common gut (and liver) microsomal CYP450s in humans were chosen for structural comparison to find the homology and identity % of D. melanogaster CYPs with that of their human counterparts. The modeled structures were validated using PROCHECK and the best fit models were used for docking several known human pharmacological agents/drugs to the modeled D. melanogaster gut CYP450s. Based on the binding affinities (ΔG values) of the selected drug molecules with the modeled fly gut CYPs, the plausible differences in metabolism of the prominent drugs in humans and flies were projected. The gut is involved in the absorption of oral drugs/pharmacological agents, and hence, upregulation of intestinal CYP450 and their reactions with endobiotics and xenobiotics is envisaged. The insights gleaned from this work can validate D. melanogaster as a model organism for studying intestinal drug metabolism, particularly in the context of a) toxicology of pharmacological agents to the gut cells and b) how gut P450 metabolites/products can influence gut homeostasis. This work can help establish a platform for further in vitro investigations on how intestinal CYP450 metabolism can influence gut health. The data from this work can be used for further in silico studies and this work can serve as a platform for future in vitro investigations on intestinal CYP450-mediated metabolism of endo- and xeno-biotics in D. melanogaster.
黑腹果蝇是发育生物学研究和癌症、阿尔茨海默病等病理生理条件研究中的重要生物。果蝇的肠道中含有几种细胞色素 P450（CYP450s），这些酶在果蝇的发育和肠道的正常生理中起着核心作用。由于这些蛋白质的晶体结构尚未被破译，我们使用 Prime（Schrödinger）对 29 种不同的黑腹果蝇肠道 CYP450 进行了结构建模。选择的黑腹果蝇肠道 CYP450 的序列与人类对应物的序列进行了比较。选择人类常见的肠道（和肝脏）微粒体 CYP450 进行结构比较，以找到与人类对应物的同源性和同一性%。使用 PROCHECK 对建模结构进行验证，并使用最佳拟合模型对几种已知的人类药理学药物/药物与建模的黑腹果蝇肠道 CYP450 进行对接。基于所选药物分子与建模的果蝇肠道 CYP450 结合的亲和力（ΔG 值），预测了人类和果蝇中重要药物代谢的可能差异。肠道参与口服药物/药理学药物的吸收，因此，预计肠道 CYP450 的上调及其与内源性和外源性物质的反应。从这项工作中获得的见解可以验证黑腹果蝇作为研究肠道药物代谢的模型生物，特别是在以下两个方面：a）药物对肠道细胞的毒理学，以及 b）肠道 P450 代谢物/产物如何影响肠道内稳态。这项工作可以为进一步的体外研究提供一个平台，研究肠道 CYP450 代谢如何影响肠道健康。这项工作的数据可以用于进一步的计算机模拟研究，并且可以作为未来在黑腹果蝇中进行肠道 CYP450 介导的内源性和外源性物质代谢的体外研究的平台。
