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Indexed by:Journal Papers

Date of Publication:2019-10-01

Journal:JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY

Included Journals:PubMed、SCIE

Volume:24

Issue:7

Page Number:1023-1033

ISSN No.:0949-8257

Key Words:DFT calculations; Cytochrome P450; Self-controlled regio-selectivity; Bioactivation mechanism; Thiophene-contained compound

Abstract:In the present work, we performed Density Functional Theory calculations to explore the bioactivation mechanism of thiophene-containing molecules mediated by P450s. For this purpose, relatively large size compounds, 2,5-diaminothiophene derivatives were selected particularly for this investigation. Here we found the successive regio-selectivity triggered by conformational turn played a significant role in the occurrence of bioactivation. 2,5-Diaminothiophene was oxidized to a 2,5-diimine thiophene-reactive intermediate by Compound I (Cpd I) through successive activations of two N-H bonds (H3-N11 and H1-N6). This reaction exhibited three special characteristics: (1) self-controlled regio-selectivity during the oxidation process. There was a large scale of conformational turn in the abstraction of the first H atom which triggers the selection of the second H for abstraction. (2) Proton-shuttle mechanism. In high spin (HS) state, proton-shuttle mechanism was observed for the abstraction of the second H atom. (3) Spin-selective manner. In protein environment, the energy barrier in HS state was much lower than that in low spin state. The novel proposed bioactivation mechanism of 2,5-diaminothiophene compounds can help us in rational design of thiophene-contained drugs avoiding the occurrence of bioactivation.