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H2O2-dependent heme depletion in ligand-free and inhibitor-bound CYP3A4. (A) Effect of series V inhibitors on the heme accessibility to H2O2. Overall, the inhibitor binding significantly protected the cofactor, and the amount of heme destroyed correlated with the Ks/IC50 values. (B) A comparative assay for CYP3A4 bound to ritonavir and the best series IV inhibitors, 5b and 7d. The heme accessibility was the lowest in CYP3A4 ligated to the high affinity/potency inhibitors, 3h and 7d.
