Next Article in Journal
Dissection of the Regulatory Elements of the Complex Expression Pattern of Puckered, a Dual-Specificity JNK Phosphatase
Next Article in Special Issue
Ligand-Based Virtual Screening Based on the Graph Edit Distance
Previous Article in Journal
Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study
Previous Article in Special Issue
Screening of β1- and β2-Adrenergic Receptor Modulators through Advanced Pharmacoinformatics and Machine Learning Approaches
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
James Adams
1,
Benjamin P. Thornton
1 and
Lydia Tabernero
1,2,3,*
1
School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
2
Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK
3
Antimicrobial Resistance Network, University of Manchester, Manchester M13 9PT, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(22), 12206; https://doi.org/10.3390/ijms222212206
Submission received: 12 October 2021 / Revised: 5 November 2021 / Accepted: 6 November 2021 / Published: 11 November 2021
(This article belongs to the Special Issue Recent Advances in Virtual Screening 2.0)

Abstract

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.
Keywords: 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); computational screening; virtual screening (VS); VSpipe; ligand efficiency indices (LEIs); drug discovery 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); computational screening; virtual screening (VS); VSpipe; ligand efficiency indices (LEIs); drug discovery

Share and Cite

MDPI and ACS Style

Adams, J.; Thornton, B.P.; Tabernero, L. A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis. Int. J. Mol. Sci. 2021, 22, 12206. https://doi.org/10.3390/ijms222212206

AMA Style

Adams J, Thornton BP, Tabernero L. A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis. International Journal of Molecular Sciences. 2021; 22(22):12206. https://doi.org/10.3390/ijms222212206

Chicago/Turabian Style

Adams, James, Benjamin P. Thornton, and Lydia Tabernero. 2021. "A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis" International Journal of Molecular Sciences 22, no. 22: 12206. https://doi.org/10.3390/ijms222212206

APA Style

Adams, J., Thornton, B. P., & Tabernero, L. (2021). A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis. International Journal of Molecular Sciences, 22(22), 12206. https://doi.org/10.3390/ijms222212206

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop