Ilia G. Denisov, Javier L. Baylon, Yelena V. Grinkova, Emad Tajkhorshid, and
Stephen G. Sligar.
Drug-drug interactions between atorvastatin and dronedarone mediated
by monomeric CYP3A4.
Biochemistry, 57:805-816, 2017.
(PMC: PMC5800941)
DENI2018-ET
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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