A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis

The kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screenin...

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Autores principales:	James Adams, Benjamin P. Thornton, Lydia Tabernero
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	protein phosphatases (PPases) phosphatase inhibitors hematopoietic protein tyrosine phosphatase (HePTP) striatum-enriched protein tyrosine phosphatase (STEP) protein tyrosine phosphatase SL (PTP-SL) kinase interaction motif protein tyrosine phosphatases (KIM-PTPs) Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ab829902ca984b639efe0a6115fa4ba4
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spelling	oai:doaj.org-article:ab829902ca984b639efe0a6115fa4ba42021-11-25T17:54:19ZA New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis10.3390/ijms2222122061422-00671661-6596https://doaj.org/article/ab829902ca984b639efe0a6115fa4ba42021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12206https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screening pipeline, to identify a ligand cluster distribution that is unique to this subfamily of PTPs. Several clusters map onto KIM-PTP specific sequence motifs in contrast to the cluster distribution obtained for PTP1B, a classic PTP that mapped to general PTP motifs. Importantly, the ligand clusters coincide with previously reported functional and substrate binding sites in KIM-PTPs. Assessment of the KIM-PTP specific clusters, using ligand efficiency index (LEI) plots generated by the VSpipe, ascertained that the binders in these clusters reside in a more drug-like chemical–biological space than those at the active site. LEI analysis showed differences between clusters across all KIM-PTPs, highlighting a distinct and specific profile for each phosphatase. The most druggable cluster sites are unexplored allosteric functional sites unique to each target. Exploiting these sites may facilitate the delivery of inhibitors with improved drug-like properties, with selectivity amongst the KIM-PTPs and over other classical PTPs.James AdamsBenjamin P. ThorntonLydia TaberneroMDPI AGarticleprotein phosphatases (PPases)phosphatase inhibitorshematopoietic protein tyrosine phosphatase (HePTP)striatum-enriched protein tyrosine phosphatase (STEP)protein tyrosine phosphatase SL (PTP-SL)kinase interaction motif protein tyrosine phosphatases (KIM-PTPs)Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12206, p 12206 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	protein phosphatases (PPases) phosphatase inhibitors hematopoietic protein tyrosine phosphatase (HePTP) striatum-enriched protein tyrosine phosphatase (STEP) protein tyrosine phosphatase SL (PTP-SL) kinase interaction motif protein tyrosine phosphatases (KIM-PTPs) Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	protein phosphatases (PPases) phosphatase inhibitors hematopoietic protein tyrosine phosphatase (HePTP) striatum-enriched protein tyrosine phosphatase (STEP) protein tyrosine phosphatase SL (PTP-SL) kinase interaction motif protein tyrosine phosphatases (KIM-PTPs) Biology (General) QH301-705.5 Chemistry QD1-999 James Adams Benjamin P. Thornton Lydia Tabernero A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
description	The kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screening pipeline, to identify a ligand cluster distribution that is unique to this subfamily of PTPs. Several clusters map onto KIM-PTP specific sequence motifs in contrast to the cluster distribution obtained for PTP1B, a classic PTP that mapped to general PTP motifs. Importantly, the ligand clusters coincide with previously reported functional and substrate binding sites in KIM-PTPs. Assessment of the KIM-PTP specific clusters, using ligand efficiency index (LEI) plots generated by the VSpipe, ascertained that the binders in these clusters reside in a more drug-like chemical–biological space than those at the active site. LEI analysis showed differences between clusters across all KIM-PTPs, highlighting a distinct and specific profile for each phosphatase. The most druggable cluster sites are unexplored allosteric functional sites unique to each target. Exploiting these sites may facilitate the delivery of inhibitors with improved drug-like properties, with selectivity amongst the KIM-PTPs and over other classical PTPs.
format	article
author	James Adams Benjamin P. Thornton Lydia Tabernero
author_facet	James Adams Benjamin P. Thornton Lydia Tabernero
author_sort	James Adams
title	A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
title_short	A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
title_full	A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
title_fullStr	A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
title_full_unstemmed	A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
title_sort	new paradigm for kim-ptp drug discovery: identification of allosteric sites with potential for selective inhibition using virtual screening and lei analysis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ab829902ca984b639efe0a6115fa4ba4
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A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis

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