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An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential
BACKGROUND: In drug discovery, a positive Ames test for bacterial mutation presents a significant hurdle to advancing a drug to clinical trials. In a previous paper, we discussed success in predicting the genotoxicity of reagent-sized aryl-amines (ArNH(2)), a structure frequently found in marketed d...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277490/ https://www.ncbi.nlm.nih.gov/pubmed/22107807 http://dx.doi.org/10.1186/1758-2946-3-51 |
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author | McCarren, Patrick Springer, Clayton Whitehead, Lewis |
author_facet | McCarren, Patrick Springer, Clayton Whitehead, Lewis |
author_sort | McCarren, Patrick |
collection | PubMed |
description | BACKGROUND: In drug discovery, a positive Ames test for bacterial mutation presents a significant hurdle to advancing a drug to clinical trials. In a previous paper, we discussed success in predicting the genotoxicity of reagent-sized aryl-amines (ArNH(2)), a structure frequently found in marketed drugs and in drug discovery, using quantum mechanics calculations of the energy required to generate the DNA-reactive nitrenium intermediate (ArNH:+). In this paper we approach the question of what molecular descriptors could improve these predictions and whether external data sets are appropriate for further training. RESULTS: In trying to extend and improve this model beyond this quantum mechanical reaction energy, we faced considerable difficulty, which was surprising considering the long history and success of QSAR model development for this test. Other quantum mechanics descriptors were compared to this reaction energy including AM1 semi-empirical orbital energies, nitrenium formation with alternative leaving groups, nitrenium charge, and aryl-amine anion formation energy. Nitrenium formation energy, regardless of the starting species, was found to be the most useful single descriptor. External sets used in other QSAR investigations did not present the same difficulty using the same methods and descriptors. When considering all substructures rather than just aryl-amines, we also noted a significantly lower performance for the Novartis set. The performance gap between Novartis and external sets persists across different descriptors and learning methods. The profiles of the Novartis and external data are significantly different both in aryl-amines and considering all substructures. The Novartis and external data sets are easily separated in an unsupervised clustering using chemical fingerprints. The chemical differences are discussed and visualized using Kohonen Self-Organizing Maps trained on chemical fingerprints, mutagenic substructure prevalence, and molecular weight. CONCLUSIONS: Despite extensive work in the area of predicting this particular toxicity, work in designing and publishing more relevant test sets for compounds relevant to drug discovery is still necessary. This work also shows that great care must be taken in using QSAR models to replace experimental evidence. When considering all substructures, a random forest model, which can inherently cover distinct neighborhoods, built on Novartis data and previously reported external data provided a suitable model. |
format | Online Article Text |
id | pubmed-3277490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32774902012-02-13 An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential McCarren, Patrick Springer, Clayton Whitehead, Lewis J Cheminform Research Article BACKGROUND: In drug discovery, a positive Ames test for bacterial mutation presents a significant hurdle to advancing a drug to clinical trials. In a previous paper, we discussed success in predicting the genotoxicity of reagent-sized aryl-amines (ArNH(2)), a structure frequently found in marketed drugs and in drug discovery, using quantum mechanics calculations of the energy required to generate the DNA-reactive nitrenium intermediate (ArNH:+). In this paper we approach the question of what molecular descriptors could improve these predictions and whether external data sets are appropriate for further training. RESULTS: In trying to extend and improve this model beyond this quantum mechanical reaction energy, we faced considerable difficulty, which was surprising considering the long history and success of QSAR model development for this test. Other quantum mechanics descriptors were compared to this reaction energy including AM1 semi-empirical orbital energies, nitrenium formation with alternative leaving groups, nitrenium charge, and aryl-amine anion formation energy. Nitrenium formation energy, regardless of the starting species, was found to be the most useful single descriptor. External sets used in other QSAR investigations did not present the same difficulty using the same methods and descriptors. When considering all substructures rather than just aryl-amines, we also noted a significantly lower performance for the Novartis set. The performance gap between Novartis and external sets persists across different descriptors and learning methods. The profiles of the Novartis and external data are significantly different both in aryl-amines and considering all substructures. The Novartis and external data sets are easily separated in an unsupervised clustering using chemical fingerprints. The chemical differences are discussed and visualized using Kohonen Self-Organizing Maps trained on chemical fingerprints, mutagenic substructure prevalence, and molecular weight. CONCLUSIONS: Despite extensive work in the area of predicting this particular toxicity, work in designing and publishing more relevant test sets for compounds relevant to drug discovery is still necessary. This work also shows that great care must be taken in using QSAR models to replace experimental evidence. When considering all substructures, a random forest model, which can inherently cover distinct neighborhoods, built on Novartis data and previously reported external data provided a suitable model. BioMed Central 2011-11-22 /pmc/articles/PMC3277490/ /pubmed/22107807 http://dx.doi.org/10.1186/1758-2946-3-51 Text en Copyright ©2011 McCarren et al; licensee Chemistry Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article McCarren, Patrick Springer, Clayton Whitehead, Lewis An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title | An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title_full | An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title_fullStr | An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title_full_unstemmed | An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title_short | An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential |
title_sort | investigation into pharmaceutically relevant mutagenicity data and the influence on ames predictive potential |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277490/ https://www.ncbi.nlm.nih.gov/pubmed/22107807 http://dx.doi.org/10.1186/1758-2946-3-51 |
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