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

Autor: Lydia Tabernero, Benjamin P. Thornton, James Adams
Rok vydání: 2021
Předmět:
QH301-705.5
MAP Kinase Signaling System
Allosteric regulation
Druggability
Computational biology
Protein tyrosine phosphatase
Ligands
Catalysis
Article
protein phosphatases (PPases)
computational screening
drug discovery
Inorganic Chemistry
Drug Delivery Systems
Humans
Biology (General)
Physical and Theoretical Chemistry
Enzyme Inhibitors
hematopoietic protein tyrosine phosphatase (HePTP)
striatum-enriched protein tyrosine phosphatase (STEP)
QD1-999
Molecular Biology
Spectroscopy
ligand efficiency indices (LEIs)
Virtual screening
Ligand efficiency
Chemistry
Drug discovery
Organic Chemistry
General Medicine
VSpipe
Ligand (biochemistry)
Computer Science Applications
virtual screening (VS)
protein tyrosine phosphatase SL (PTP-SL)
kinase interaction motif protein tyrosine phosphatases (KIM-PTPs)
phosphatase inhibitors
Protein Tyrosine Phosphatases
Sequence motif
Allosteric Site
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 12206, p 12206 (2021)
Volume 22
Issue 22
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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