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.
Highlights
Protein tyrosine phosphatases (PTPs) are fundamental regulators of numerous biological pathways and important therapeutic targets for multiple diseases [1,2,3,4,5,6]
We recently reported the use of the virtual screening tool, VSpipe [29], to effectively identify functional ligand binding sites on PTP1B, including an allosteric inhibitor site, and on fungal phosphatases [30]
The receptor models for the three KIM-PTPs used in this study were all in the open conformation and obtained from crystallographic structures deposited in the protein data bank for protein tyrosine phosphatase SL (PTP-SL) (PDB ID: 1JLN), striatum-enriched protein tyrosine phosphatase (STEP) (PDB ID: 2BV5) and hematopoietic protein tyrosine phosphatase (HePTP) (PDB ID: 3O4U)
Summary
Protein tyrosine phosphatases (PTPs) are fundamental regulators of numerous biological pathways and important therapeutic targets for multiple diseases [1,2,3,4,5,6]. KIM-PTPs are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways [7,8,9,10], and represent important therapeutic targets for cancer [11,12], or neurodegenerative diseases [13,14]. Given their therapeutic importance, several investigations into their inhibition have been undertaken [15,16,17,18], together with their activation [19]. Focus has turned to target regulatory mechanisms, including allosteric regulation, protein oligomerisation and redox modulation [21,22,23]
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