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

Abstract

With advances in the development and application of Ames mutagenicity in silico 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.

Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

“…While there are drugs, including propranolol, that contain a naphthalene core, naphthalenes have been identified as a minor mutagenic scaffold in the Ames Mutagenicity Tree. 36 A related naphthalene 4 , RA-839, showed in vivo activity only if Phase 1 metabolism were blocked. Although the identity of the RA-839 metabolites are unknown, they may include reactive intermediates, as naphthalenes are known to be metabolically activated to reactive naphthalene oxides and naphthoquinones.…”

In silico toxicology: From structure–activity relationships towards deep learning and adverse outcome pathways

“…A new method, which is able to partly incorporate such modifications is the generation of structural alerts through scaffold trees . The generated trees show how the hazard of a molecule changes when the parent fragment is modified.…”

“…71,72 A new method, which is able to partly incorporate such modifications is the generation of structural alerts through scaffold trees. 73 The generated trees show how the hazard of a molecule changes when the parent fragment is modified. When assessing a compound with structural alerts it is important to understand the absence of an alert does not denote a molecule to be nontoxic, rather it states no known alert could be found.…”

Molecular Docking Study of Anthocyanidin Compounds Against Epidermal Growth Factor Receptor (EGFR) as Anti-Lung Cancer

“…Respon mutagenik pada senyawa mutagen tergantung dari struktur kimia senyawa mutagen. 21 Untuk itulah diperlukan penelitian lanjutan untuk menghilangkan sifat mutagenik tersebut dengan memodifikasi struktur kimia yang bersifat mutagen pada senyawa-senyawa antosianidin.…”