Structural Modeling of Drosophila melanogaster Gut Cytochrome P450s and Docking Comparison of Fruit Fly Gut and Human Cytochrome P450s,Current Drug Metabolism

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Structural Modeling of Drosophila melanogaster Gut Cytochrome P450s and Docking Comparison of Fruit Fly Gut and Human Cytochrome P450s
Current Drug Metabolism ( IF 2.1 ) Pub Date : 2022-05-12 , DOI: 10.2174/1389200223666220511162234
Vijay Nirusimhan ₁ , Daniel Andrew Gideon ₂ , Abhinav Parashar ₃ , Sangavi Jeyachandran ₁ , Jeyakanthan Jeyaraman ₄ , Gowthamkumar Subbaraj ₅ , Langeswaran Kulanthaivel ₁

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: 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.

中文翻译：

果蝇肠道细胞色素 P450s 的结构建模和果蝇肠道与人类细胞色素 P450s 的对接比较

：黑腹果蝇是发育生物学研究以及癌症和阿尔茨海默氏病等病理生理学相关研究中的重要生物体。果蝇肠道含有多种细胞色素 P450 (CYP450)，它们在果蝇发育和肠道正常生理学中起着重要作用。由于尚未破译这些蛋白质的晶体结构，我们使用 Prime (Schrödinger) 模拟了 29 种不同的黑腹果蝇肠道 CYP450 的结构。将所选 D. melanogaster 肠道 CYP450 的序列与其人类对应物的序列进行比较。选择人类常见的肠道（和肝脏）微粒体 CYP450 进行结构比较，以发现黑腹果蝇 CYP 与其人类对应物的同源性和同一性百分比。使用 PROCHECK 验证建模结构，并使用最合适的模型将几种已知的人类药理剂/药物与建模的黑腹果蝇肠道 CYP450 对接。基于所选药物分子与模拟的果蝇肠道 CYP 的结合亲和力（ΔG 值），预测了主要药物在人类和果蝇中代谢的合理差异。肠道参与口服药物/药剂的吸收，因此，可以设想上调肠道 CYP450 及其与内生素和异生素的反应。从这项工作中收集到的见解可以验证 D. melanogaster 作为研究肠道药物代谢的模式生物，特别是在 a) 药物制剂对肠道细胞的毒理学和 b) 肠道 P450 代谢物/产物如何影响肠道稳态的背景下。这项工作有助于建立一个平台，进一步研究肠道 CYP450 代谢如何影响肠道健康。这项工作的数据可用于进一步的计算机研究，并且这项工作可以作为未来体外研究黑腹果蝇肠道 CYP450 介导的内源性和异源性生物代谢的平台。

更新日期：2022-05-12

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