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Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis

Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to si...

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Autores principales: Wang, Rui, Xu, Jian, Yan, Rong, Liu, Huanbin, Zhao, Jingxin, Xie, Yuan, Deng, Wenbin, Liao, Weiping, Nie, Yichu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9493029/
https://www.ncbi.nlm.nih.gov/pubmed/36160399
http://dx.doi.org/10.3389/fphar.2022.998245
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author Wang, Rui
Xu, Jian
Yan, Rong
Liu, Huanbin
Zhao, Jingxin
Xie, Yuan
Deng, Wenbin
Liao, Weiping
Nie, Yichu
author_facet Wang, Rui
Xu, Jian
Yan, Rong
Liu, Huanbin
Zhao, Jingxin
Xie, Yuan
Deng, Wenbin
Liao, Weiping
Nie, Yichu
author_sort Wang, Rui
collection PubMed
description Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity.
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spelling pubmed-94930292022-09-23 Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis Wang, Rui Xu, Jian Yan, Rong Liu, Huanbin Zhao, Jingxin Xie, Yuan Deng, Wenbin Liao, Weiping Nie, Yichu Front Pharmacol Pharmacology Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity. Frontiers Media S.A. 2022-09-08 /pmc/articles/PMC9493029/ /pubmed/36160399 http://dx.doi.org/10.3389/fphar.2022.998245 Text en Copyright © 2022 Wang, Xu, Yan, Liu, Zhao, Xie, Deng, Liao and Nie. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Rui
Xu, Jian
Yan, Rong
Liu, Huanbin
Zhao, Jingxin
Xie, Yuan
Deng, Wenbin
Liao, Weiping
Nie, Yichu
Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title_full Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title_fullStr Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title_full_unstemmed Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title_short Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
title_sort virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9493029/
https://www.ncbi.nlm.nih.gov/pubmed/36160399
http://dx.doi.org/10.3389/fphar.2022.998245
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