Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors

Abstract Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits...

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Autores principales:	Seketoulie Keretsu, Suparna Ghosh, Seung Joo Cho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/064aa1af3b8144639f85b32b9b179cb3
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spelling	oai:doaj.org-article:064aa1af3b8144639f85b32b9b179cb32021-12-05T12:15:22ZComputer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors10.1038/s41598-021-02364-22045-2322https://doaj.org/article/064aa1af3b8144639f85b32b9b179cb32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02364-2https://doaj.org/toc/2045-2322Abstract Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits signals from the interleukin-2, interleukin-4, gp130, and class 2 receptor families. It is ubiquitously expressed in humans and its overexpression has been linked with autoimmune diseases such as myeloproliferative neoplasm. Although JAK1 inhibitors such as Tofacitinib have been approved for medical use, the low potency and off-target effects of these inhibitors have limited their use and calls for the development of novel JAK1 inhibitors. In this study, we used computational methods on a series of pyrrolopyridine derivatives to design new JAK1 inhibitors. Molecular docking and molecular dynamics simulation methods were used to study the protein-inhibitor interactions. 3D-quantitative structure–activity relationship models were developed and were used to predict the activity of newly designed compounds. Free energy calculation methods were used to study the binding affinity of the inhibitors with JAK1. Of the designed compounds, seventeen of the compounds showed a higher binding energy value than the most active compound in the dataset and at least six of the compounds showed higher binding energy value than the pan JAK inhibitor Tofacitinib. The findings made in this study could be utilized for the further development of JAK1 inhibitors.Seketoulie KeretsuSuparna GhoshSeung Joo ChoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Seketoulie Keretsu Suparna Ghosh Seung Joo Cho Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
description	Abstract Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits signals from the interleukin-2, interleukin-4, gp130, and class 2 receptor families. It is ubiquitously expressed in humans and its overexpression has been linked with autoimmune diseases such as myeloproliferative neoplasm. Although JAK1 inhibitors such as Tofacitinib have been approved for medical use, the low potency and off-target effects of these inhibitors have limited their use and calls for the development of novel JAK1 inhibitors. In this study, we used computational methods on a series of pyrrolopyridine derivatives to design new JAK1 inhibitors. Molecular docking and molecular dynamics simulation methods were used to study the protein-inhibitor interactions. 3D-quantitative structure–activity relationship models were developed and were used to predict the activity of newly designed compounds. Free energy calculation methods were used to study the binding affinity of the inhibitors with JAK1. Of the designed compounds, seventeen of the compounds showed a higher binding energy value than the most active compound in the dataset and at least six of the compounds showed higher binding energy value than the pan JAK inhibitor Tofacitinib. The findings made in this study could be utilized for the further development of JAK1 inhibitors.
format	article
author	Seketoulie Keretsu Suparna Ghosh Seung Joo Cho
author_facet	Seketoulie Keretsu Suparna Ghosh Seung Joo Cho
author_sort	Seketoulie Keretsu
title	Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
title_short	Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
title_full	Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
title_fullStr	Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
title_full_unstemmed	Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors
title_sort	computer aided designing of novel pyrrolopyridine derivatives as jak1 inhibitors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/064aa1af3b8144639f85b32b9b179cb3
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_version_	1718372056227119104

Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors

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