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. 2018 Feb 6;57(5):805-816.
doi: 10.1021/acs.biochem.7b01012. Epub 2017 Dec 14.

Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4

Ilia G Denisov  1 , Javier L Baylon  1 , Yelena V Grinkova  1 , Emad Tajkhorshid  1 , Stephen G Sligar  1
Affiliations

Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4

Ilia G Denisov et al. Biochemistry. .

Abstract

Heterotropic interactions between atorvastatin (ARVS) and dronedarone (DND) have been deciphered using global analysis of the results of binding and turnover experiments for pure drugs and their mixtures. The in vivo presence of atorvastatin lactone (ARVL) was explicitly taken into account by using pure ARVL in analogous experiments. Both ARVL and ARVS inhibit DND binding and metabolism, while a significantly higher affinity of CYP3A4 for ARVL makes the latter the main modulator of activity (effector) in this system. Molecular dynamics simulations reveal significantly different modes of interactions of DND and ARVL with the substrate binding pocket and with a peripheral allosteric site. Interactions of both substrates with residues F213 and F219 at the allosteric site play a critical role in the communication of conformational changes induced by effector binding to productive binding of the substrate at the catalytic site.

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Figures

Figure 1
Figure 1
Schematic model of cytochrome P450 CYP3A4 inserted in the membrane. CYP3A4 structure with progesterone (orange sticks) bound at the peripheral site (pdb file 1W0F (30)) is shown in cartoon representation with heme shown in red sticks, Membrane insertion is schematically drawn according to MD simulations ((1, 31)). Amino acids of F-F′ (magenta) and G-G′ (green) loops in direct contact with progesterone are highlighted as surfaces. Substrate binding cavity near catalytic site is shown as blue surface.
Figure 2
Figure 2
Structures of substrates ARVS and DND with the main sites of metabolism in CYP3A4 indicated with asterisks.
Figure 3
Figure 3
Global analysis of CYP3A4 metabolism of ATVS. NADPH oxidation rates (circles), product formation rates (triangles) and percent of high spin (diamonds) are fitted as a function of substrate concentrations as described in Methods section. Rate of NADPH consumption is scaled by a factor of 20 to match the plot limit.
Figure 4
Figure 4
Global analysis of CYP3A4 metabolism of ARVL. Symbols are the same as in Figure 3. Rate of NADPH consumption is scaled by a factor of 20 to match the plot limit.
Figure 5
Figure 5
Global analysis of CYP3A4 metabolism of DND. Symbols are the same as in Figure 3 and 4. Rate of NADPH consumption is scaled by a factor of 10 to match the plot limit.
Figure 6
Figure 6
Global analysis of turnover in the mixture of: (A) ARVS (triangles) and DND (circles); (B) ARVL (squares) and DND (circles).
Figure 7
Figure 7
Summary of the results of the global analysis of CYP3A4 metabolism of mixtures of DND with ATVS and ATVL
Figure 8
Figure 8
Change in F-F′ loop in the presence of a drug in the productive site of CYP3A4. (Top) Time series of the backbone RMSD of the F-F′ loop of CYP3A4 (residues 209 to 218), calculated for System 1 and System 2 (Table 1). For the RMSD, the structure of our membrane-bound model of CYP3A4 reported in [1] was employed. (Bottom) Initial and final snapshots of ARVL and DND in the active site of CYP3A4 obtained from molecular docking and MD simulations. Protein in shown in cartoon representation, with the F-F′ loop highlighted in orange or magenta color for ARVL or DND simulations, respectively. The dashed line represents the average location of the membrane in the simulated systems. The drug, heme and important residues are shown in in stick representation. The iron of the heme and the sites of metabolism of each drug are shown as spheres.
Figure 9
Figure 9
Effect of the lipid bilayer on drug binding at the allosteric site of CYP3A4. Representative snapshots (i.e., most observed configuration during the simulations) of ARVL (left) and DND (right) bound in the allosteric site of CYP3A4. For the membrane simulations, protein, drug and Phe-219 side chain are shown using the same scheme as in Fig. 1. For the control simulations without the membrane, protein and drug are shown as blue cartoon and sticks, respectively.
Figure 10
Figure 10
Membrane-bound CYP3A4 with drugs in the productive and allosteric binding sites. Representative snapshots of CYP3A4 bound to two drug molecules. Dashed line represents the average location of the membrane in the simulations. Protein, drugs and key side chains are shown following the same scheme as described in Fig. 1. The iron of the heme and the sites of metabolism of drugs in the productive site are shown as spheres.
Figure 11
Figure 11
Dynamics of Phe-213 in drug-binding simulations. Time series of the center-of-mass distance of the Phe-213 side chain and the heme in out MD simulations. The dashed line indicates the average reference distance of 14.7 Å calculated from the apo membrane-bound CYP3A4 simulation, as we previously reported(1)
Scheme 1
Scheme 1
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