Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.

Drug-induced liver injury (DILI) is one of major causes of discontinuing drug development and withdrawing drugs from the market. In this study, we investigated chemical properties associated with DILI using in silico methods, to identify a physicochemical property useful for DILI screening at the ea...

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Autores principales:	Yuki Shimizu, Takamitsu Sasaki, Jun-Ichi Takeshita, Michiko Watanabe, Ryota Shizu, Takuomi Hosaka, Kouichi Yoshinari
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fb7e98ec58904b5a8321109eb83cbaed
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spelling	oai:doaj.org-article:fb7e98ec58904b5a8321109eb83cbaed2021-12-02T20:09:57ZIdentification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.1932-620310.1371/journal.pone.0253855https://doaj.org/article/fb7e98ec58904b5a8321109eb83cbaed2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253855https://doaj.org/toc/1932-6203Drug-induced liver injury (DILI) is one of major causes of discontinuing drug development and withdrawing drugs from the market. In this study, we investigated chemical properties associated with DILI using in silico methods, to identify a physicochemical property useful for DILI screening at the early stages of drug development. Total of 652 drugs, including 432 DILI-positive drugs (DILI drugs) and 220 DILI-negative drugs (no-DILI drugs) were selected from Liver Toxicity Knowledge Base of US Food and Drug Administration. Decision tree models were constructed using 2,473 descriptors as explanatory variables. In the final model, the descriptor AMW, representing average molecular weight, was found to be at the first node and showed the highest importance value. With AMW alone, 276 DILI drugs (64%) and 156 no-DILI drugs (71%) were correctly classified. Discrimination with AMW was then performed using therapeutic category information. The performance of discrimination depended on the category and significantly high performance (>0.8 balanced accuracy) was obtained in some categories. Taken together, the present results suggest AMW as a novel descriptor useful for detecting drugs with DILI risk. The information presented may be valuable for the safety assessment of drug candidates at the early stage of drug development.Yuki ShimizuTakamitsu SasakiJun-Ichi TakeshitaMichiko WatanabeRyota ShizuTakuomi HosakaKouichi YoshinariPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253855 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuki Shimizu Takamitsu Sasaki Jun-Ichi Takeshita Michiko Watanabe Ryota Shizu Takuomi Hosaka Kouichi Yoshinari Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
description	Drug-induced liver injury (DILI) is one of major causes of discontinuing drug development and withdrawing drugs from the market. In this study, we investigated chemical properties associated with DILI using in silico methods, to identify a physicochemical property useful for DILI screening at the early stages of drug development. Total of 652 drugs, including 432 DILI-positive drugs (DILI drugs) and 220 DILI-negative drugs (no-DILI drugs) were selected from Liver Toxicity Knowledge Base of US Food and Drug Administration. Decision tree models were constructed using 2,473 descriptors as explanatory variables. In the final model, the descriptor AMW, representing average molecular weight, was found to be at the first node and showed the highest importance value. With AMW alone, 276 DILI drugs (64%) and 156 no-DILI drugs (71%) were correctly classified. Discrimination with AMW was then performed using therapeutic category information. The performance of discrimination depended on the category and significantly high performance (>0.8 balanced accuracy) was obtained in some categories. Taken together, the present results suggest AMW as a novel descriptor useful for detecting drugs with DILI risk. The information presented may be valuable for the safety assessment of drug candidates at the early stage of drug development.
format	article
author	Yuki Shimizu Takamitsu Sasaki Jun-Ichi Takeshita Michiko Watanabe Ryota Shizu Takuomi Hosaka Kouichi Yoshinari
author_facet	Yuki Shimizu Takamitsu Sasaki Jun-Ichi Takeshita Michiko Watanabe Ryota Shizu Takuomi Hosaka Kouichi Yoshinari
author_sort	Yuki Shimizu
title	Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
title_short	Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
title_full	Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
title_fullStr	Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
title_full_unstemmed	Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
title_sort	identification of average molecular weight (amw) as a useful chemical descriptor to discriminate liver injury-inducing drugs.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/fb7e98ec58904b5a8321109eb83cbaed
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Identification of average molecular weight (AMW) as a useful chemical descriptor to discriminate liver injury-inducing drugs.

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