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Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Stohner, Jürgen

12 Issues per year


IMPACT FACTOR 2016: 2.626
5-year IMPACT FACTOR: 3.210

CiteScore 2017: 3.42

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Source Normalized Impact per Paper (SNIP) 2017: 1.546

Online
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1365-3075
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Volume 89, Issue 10

Issues

Integral estimation of xenobiotics’ toxicity with regard to their metabolism in human organism

Alexander Dmitriev / Anastasia Rudik / Dmitry Filimonov / Alexey Lagunin
  • Institute of Biomedical Chemistry, 10 bldg. 7 Pogodinskaya Str., Moscow 119121, Russia
  • Medico-biological Faculty, Pirogov Russian National Research Medical University, 1 Ostrovityanova Str., Moscow 117997, Russia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Pavel Pogodin / Varvara Dubovskaja / Vladislav Bezhentsev / Sergey Ivanov
  • Institute of Biomedical Chemistry, 10 bldg. 7 Pogodinskaya Str., Moscow 119121, Russia
  • Medico-biological Faculty, Pirogov Russian National Research Medical University, 1 Ostrovityanova Str., Moscow 117997, Russia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Dmitry Druzhilovsky / Olga Tarasova / Vladimir Poroikov
Published Online: 2017-07-25 | DOI: https://doi.org/10.1515/pac-2016-1205

Abstract

Toxicity and severe adverse effects are the primary cause of drug-candidate failures at the late stages of preclinical and clinical trials. Since most xenobiotics undergo biotransformations, their interaction with human organism reveals the effects produced by parent compounds and all metabolites. To increase the chances of successful drug development, estimation of the entire toxicity for drug substance and its metabolites is necessary for filtering out the potentially toxic compounds. We proposed the computational approach to the integral evaluation of xenobiotics’ toxicity based on the structural formula of the drug-like compound. In the framework of this study, the consensus QSAR model was developed based on the analysis of over 3000 compounds with information about their rat acute toxicity for intravenous route of administration. Four different numerical methods, estimating the integral toxicity, were proposed, and their comparative performance was studied using the external evaluation set consisting of 37 structures of drugs and 200 their metabolites. It was shown that, on the average, the best correspondence between the predicted and published data is obtained using the method that takes into account the estimated characteristics for both the parent compound and its most toxic metabolite.

This article offers supplementary material which is provided at the end of the article.

Keywords: computational predictions; drug substance; integral evaluation; metabolites; Mendeleev XX; xenobiotics toxicity

Article note:

A collection of invited papers based on presentations at the XX Mendeleev Congress on General and Applied Chemistry (Mendeleev XX), held in Ekaterinburg, Russia, September 25–30, 2016.

References

About the article

Published Online: 2017-07-25

Published in Print: 2017-09-26


Funding Source: Russian Science Foundation

Award identifier / Grant number: 14-15-00449

The Russian Science Foundation (grant No. 14-15-00449) has supported the work.


Citation Information: Pure and Applied Chemistry, Volume 89, Issue 10, Pages 1449–1458, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2016-1205.

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©2017 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/.Get Permission

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