Fig. 1. Small molecules dock on human POR and regulate electron transfer in vitro.

A POR is the omnipotent electron donor to all CYPs in the ER membrane, activating metabolic cascades in both human and plants by transferring electrons to redox partners. Targeting POR with small-molecule ligands may bias metabolic outcomes and regulate basic metabolism in humans or tune the formation of natural products in plants. B Molecular structures of small-molecule ligands and their respective binding. Ligands (green) were docked on human POR with cofactors (yellow) in a compact conformation (PDB 3QE2) in Sites Ia and Ib determined from SiteMap analysis (see Supplementary Fig. 3A and Supplementary Table 1). Insets display the predicted binding conformations of cyclophosphamide (a + d), dhurrin (b + e), and rifampicin (c). See Supplementary Figs. 3–5 for higher magnification and detailed interactions and Supplementary Table 2 for binding energies. C In vitro activity of human POR proteoliposomes measured by the commonly used Cytc assay²⁹. D Ligands bias human POR capacity to reduce Cytc in proteoliposomes at 100 μM, acting either as agonist (cyclophosphamide) or inverse agonizts (dhurrin and rifampicin). The bar plot represents the mean ± SD of independent replicates (n = 2–3; see Supplementary Table 3 for exact value of n for each experimental condition). Overlapping data points appear shaded. Level of significance is determined by one-way ANOVA and Tukey’s HSD test correcting for multiple comparisons (*p < 0.05; **p < 0.01; ***p < 0.005; see Supplementary Methods and Supplementary Table 3 for details). Source data are provided as a Source Data file.