Will 1,2-dihydro-1,2-azaborine-based drugs resist metabolism by cytochrome P450 compound I?
- Published
- Accepted
- Subject Areas
- Biochemistry, Biophysics
- Keywords
- reaction mechanism, P450, xenobiotics, azaborine, bioisostere
- Copyright
- © 2016 Silva
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ Preprints) and either DOI or URL of the article must be cited.
- Cite this article
- 2016. Will 1,2-dihydro-1,2-azaborine-based drugs resist metabolism by cytochrome P450 compound I? PeerJ Preprints 4:e1989v2 https://doi.org/10.7287/peerj.preprints.1989v2
Abstract
1,2-dihydro-1,2-azaborine is a structural and electronic analogue of benzene which is able to occupy benzene-binding pockets in T4 lysozyme and has been proposed as suitable arene-mimicking group for biological and pharmaceutical applications. Its applicability in a biological context requires it to be able to resist modification by xenobiotic-degrading enzymes like the P450 cytochromes. Quantum chemical computations described in this work show that 1,2-dihydro-1,2-azaborine is much more prone to modification by these enzymes than benzene, unless steric crowding of the ring prevents it from reaching the active site, or otherwise only allows reaction at the very sluggish C4-position. This novel heterocyclic compound is therefore expected to be of limited usefulness as an aryl bioisostere.
Author Comment
The last portion of the results has been rewritten for clarity. Tables 2 and 3 now also state whether the reaction product analysed is an epoxide, a sigma adduct or 3 H -1,3,2-oxazaborepine. This version was submitted to PeerJ on May 16th, 2016.
Supplemental Information
Single-point energies computed with different basis sets, ZPVE, -D3 corrections, etc
Geometries of all intermediates, in .xyz
These geometries may be visualized with most common molecular viewers (Molden, ChemCraft, YASARA, Mercury, etc.)