Mutagenicity in a Molecule: Identification of Core Structural Features of Mutagenicity Using a Scaffold Analysis

<div><p>With advances in the development and application of Ames mutagenicity <i>in silico</i> prediction tools, the International Conference on Harmonisation (ICH) has amended its M7 guideline to reflect the use of such prediction models for the detection of mutagenic activity in early drug safety evaluation processes. Since current Ames mutagenicity prediction tools only focus on functional group alerts or side chain modifications of an analog series, these tools are unable to identify mutagenicity derived from core structures or specific scaffolds of a compound. In this study, a large collection of 6512 compounds are used to perform scaffold tree analysis. By relating different scaffolds on constructed scaffold trees with Ames mutagenicity, four major and one minor novel mutagenic groups of scaffold are identified. The recognized mutagenic groups of scaffold can serve as a guide for medicinal chemists to prevent the development of potentially mutagenic therapeutic agents in early drug design or development phases, by modifying the core structures of mutagenic compounds to form non-mutagenic compounds. In addition, five series of substructures are provided as recommendations, for direct modification of potentially mutagenic scaffolds to decrease associated mutagenic activities.</p></div

The scaffold structures of minor mutagenic scaffold groups.

<p>(A) Naphthalene, (B) Quinoline, and (C) Bezene groups. Below the labels of scaffold names were labelled by the mutagen rates and the numbers of mutagen compounds/the numbers of overall compounds in that scaffolds. In the structures of child scaffolds, the differences from the parent scaffold were colored as red.</p

The scaffold structures of examples of sibling relationships between mutagenic scaffolds and non-mutagenic scaffolds.

<p>(A) Acridine, (B) Phenanthrene, (C) Quinoxaline, (D) Naphthalene, and (E) Quinoline groups. Below the labels of scaffold names were labelled by the mutagen rates and the numbers of mutagen compounds/the numbers of overall compounds in that scaffolds. In the structures of child scaffolds, the differences from the parent scaffold were colored as red.</p

The scaffold structures of major mutagenic scaffold groups.

<p>(A) Acridine, (B) Phenanthene, (C) Pyrene, and (D) Quinoxaline groups. Below the labels of scaffold names were labelled by the mutagen rates and the numbers of mutagen compounds/the numbers of overall compounds in that scaffolds. In the structures of child scaffolds, the differences from the parent scaffold were colored as red. The mutagenicities shown in Fig 1 were presented as the percentage of mutagenic compounds for each scaffold, and the IUPAC names were generated using the Chemaxon Marvin applet.[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0148900#pone.0148900.ref030" target="_blank">30</a>].</p

The Toxtree prediction results.

<p>(A) 5-(bromomethyl)-2,3-dimethoxyquinoxaline and (B) acridiine-1,9-diamine. The fitted structural alerts were labelled.</p

The C/S distribution plots according to different mutagenicity cutoff values.

<p>(A) In selecting mutagenic scaffolds, using the mutagens categorized in each selected scaffold as the selection criteria (C₁/S). The detailed scores were listed in <b>Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0148900#pone.0148900.s001" target="_blank">S1 File</a></b>. (B) In selecting non-mutagenic scaffolds, using the non-mutagens categorized in each selected scaffold as the selection criteria (C₂/S). The detailed scores were listed in <b>Table B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0148900#pone.0148900.s001" target="_blank">S1 File</a>.</b> (C₁: number of mutagenic compounds, C₂: number of non-mutagenic compounds, S: number of mutagenic (for C₁) or non-mutagenic (for C₂) scaffolds).</p

Modeling the CH Stretch/Torsion/Rotation Couplings in Methyl Peroxy (CH₃OO)

The manifestations of CH stretch/torsion/rotation coupling in the region of the CH stretch fundamentals are explored in the CH₃OO radical. Following our earlier study of the fundamental in the totally symmetric CH stretch (the ν₂ fundamental), this work focuses on the other two CH stretch fundamentals, ν₁ and ν₉, which would be degenerate in the absence of a barrier in the potential along the methyl torsion coordinate. The simplest model, which assumes a decoupling of the CH stretch vibrations from the torsion, fails to reproduce several important features of the spectrum. Specifically, the absence of a strong peak around the origin of the ν₁ fundamental and broadening of the strong peak near the origin in the observed spectrum of the ν₉ fundamental are not captured by this model. The origins of these features are explored through two more sophisticated treatments of the torsion/CH stretch couplings. In the first, a four-dimensional potential based on the three CH stretches and the torsion is developed and shown to reproduce both of these features. On the basis of the results of these calculations, the calculated parameters are adjusted to simulate the recorded spectrum. To further explore the torsion/CH stretch couplings in CH₃OO, a 9-state model Hamiltonian is developed and discussed. The implications of various types of couplings on the observed energy level patterns are also discussed