A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
AuthorsAdams, James; email: firstname.lastname@example.org
Thornton, Benjamin P.; email: email@example.com
Tabernero, Lydia; orcid: 0000-0001-8867-455X; email: Lydia.Tabernero@manchester.ac.uk
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AbstractThe 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.
CitationInternational Journal of Molecular Sciences, volume 22, issue 22, page e12206
DescriptionFrom MDPI via Jisc Publications Router
History: accepted 2021-11-06, pub-electronic 2021-11-11
Publication status: Published
Funder: Biotechnology and Biological Sciences Research Council; Grant(s): Doctoral Training Partnership PhD studentship
Funder: University of Manchester; Grant(s): Presidential PhD award
Funder: Medical Research Council; Grant(s): Doctoral Training Partnership PhD studentship
Funder: Society for Chemical Industry; Grant(s): scholarship
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