Molecular dynamics and density functional studies on the metabolic selectivity of antipsychotic thioridazine by cytochrome P450 2D6: Connection with crystallographic and metabolic results.
CYP2D6, a cytochrome P450 isoform, significantly contributes to the metabolism of many clinically important drugs. Thioridazine (THD) is one of the phenothiazine-type antipsychotics, which exhibit dopamine D2 antagonistic activity. THD shows characteristic metabolic profiles compared to other phenothiazine-type antipsychotics such as chlorpromazine. The sulfur atom attached to the phenothiazine ring is preferentially oxidized mainly by CYP2D6, that is, the 2-sulfoxide is a major metabolite, and interestingly this metabolite shows more potent activity against dopamine D2 receptors than THD. On the other hand, the formation of this metabolite causes many serious problems for its clinical use. Wójcikowski et al. (Drug Metab. Dispos. 2006, 34, 471) reported a kinetic study of THD formed by CYP2D6. Recently, Wang et al. (J. Biol. Chem. 2012, 287, 10834 and J. Biol. Chem. 2015, 290, 5092) revealed the crystallographic structure of THD with CYP2D6. In the current study, the binding and reaction mechanisms at the atomic and electronic levels were computationally examined based on the assumption as to whether or not the different crystallographic binding poses correspond to the different metabolites. The binding and oxidative reaction steps in the whole metabolic process were investigated using molecular dynamics and density functional theory calculations, respectively. The current study demonstrated the essential importance of the orientation of the substrate in the reaction center of CYP2D6 for the metabolic reaction.
Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan; Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan.
Katsunori
K
Sasahara
Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
Akira
A
Mashima
Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
Tatsusada
T
Yoshida
Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan. Electronic address: hchuman@tokushima-u.ac.jp.
Hiroshi
H
Chuman
D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D013881:Thioridazine / Q000378:metabolism* / Q000494:pharmacology
D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D013881:Thioridazine
Activation energy (E(a)); Binding orientation; Compound I (Cpd I); Crystallographic structure; Cytochrome P450 2D6 (CYP2D6); Density functional theory (DFT); Mesoridazine; Molecular dynamics (MD); Sites of metabolism (SOM); Sulforidazine; Thioridazine (THD); Transition state (TS)