Article
Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations.
Biochemistry - 27 Jan 2015
Müller Christian S, Knehans Tim, Davydov Dmitri R, Bounds Patricia L, von Mandach Ursula, Halpert James R, Caflisch Amedeo, Koppenol Willem H
Abstract excerpt
Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in...
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