Fig. 2: The C-terminal loop plays an important role in selective CYP3A4 inhibition.

a–c Concentration-dependent inhibition of CYP3A4 and CYP3A5 for (a) SCM-01, (b) SCM-02, and (c) SCM-03, respectively. Percentage inhibition data were normalized against their DMSO controls (as 0% inhibition) and against 30 µM ketoconazole controls (as 100% inhibition). The reported numerical values are the means and standard deviations of the IC₅₀ values derived from triplicate experiments (n = 3). d–f Crystal structures of CYP3A4 in complex with (d) SCM-01, (e) SCM-02, and (f) SCM-03 highlighting the interactions between ligands and adjacent residues. g Superimposition of the three selective inhibitor–bound CYP3A4 crystal structures (green, blue, and pink) and all five published CYP3A5 structures (yellow), showing that the selective inhibitors would clash with the CYP3A5 C-terminal loop (circled region, purple) if bound to CYP3A5 in the same conformation as CYP3A4. h Representative CYP3A5-apo crystal structure showing H-bonds associated with the C-terminal loop residues. i Representative CYP3A4–SCM-01 crystal structure showing that the D214-G481 is the only H-bond associated with the C-terminal loop in CYP3A4. The inset shows the sequence alignment of C-terminal loop residues in CYP3A4 and CYP3A5. The heme groups in all panels are colored in wheat. Source data for (a–c) are provided as a Source Data file.