Figure 7.

A-D, Chemical structures of ritonavir, deaza-ritonavir, DTMCR, and cobicistat, respectively. The heme-ligating primary amino group and thiazole nitrogens are shown in red. E, Ritonavir (magenta) bound to the active site of CYP3A4 (3NXU structure).⁵⁴ Phenylalanine residues surrounding ritonavir are in green, whereas residues comprising the polar ‘umbrella’, a cluster of charged residues connected to the isopropyl moiety via a water molecule (cyan sphere), and the H-bond forming Ser119 are in yellow. F, Superposition of the ritonavir-(magenta, pink and gray) and DTMCR-bound (cyan, light cyan and yellow; 3TJS)³³ structures of CYP3A4. To optimize hydrophobic interactions via phenyl side groups, DTMCR rotates by 180° relative to ritonavir. Since DTMCR is shorter than ritonavir, it cannot interact with the polar ‘umbrella’ and F-F’ loop. As a result, the F-F’ loop becomes disordered and the active site is solvent accessible in the DTMCR-bound structure. Also, DTMCR has differently oriented phenyl groups and does not clash with the 369-370 peptide. This is in contrast to the CYP3A4-ritonavir complex, where the heme shifts downwards and the Fe-N bond is slightly elongated because of steric hindrance with the 369-370 peptide.