Structural Modeling of Drosophila melanogaster Gut Cytochrome P450s and Docking Comparison of Fruit Fly Gut and Human Cytochrome P450s

Abstract

Abstract: 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.