Interaction of human cytochrome P4503A4 with ritonavir analogs

► We compared the interaction of CYP3A4 with the inhibitor ritonavir and two analogs. ► Peripheral binding of ritonavir limits and complicates the heme ligation kinetics. ► Active site residue Arg212 assists binding of ritonavir-like molecules to CYP3A4. ► CYP3A4-desthiazolylmethyloxycarbonyl ritonavir complex structure is determined. ► Structural data suggest how the inhibitory potency of ritonavir can be improved.