Druggability analysis and classification of protein tyrosine phosphatase active sites

Abstract

Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability. Particularly focusing on PTP1B, we also demonstrated the influence of several factors on the druggability of PTP active site. For instance, the open conformation showed better druggability than the closed conformation, while the tight-bound water molecules appeared to have minimal effect on the PTP1B druggability. Finally, the allosteric site of PTP1B was found to exhibit superior druggability compared to the catalytic pocket. This analysis can prove useful in the discovery of new PTP inhibitors by assisting researchers in predicting hit rates from high throughput or virtual screening and saving unnecessary cost, time, and efforts via prioritizing PTP targets according to their predicted druggability.

MptpB Promotes Mycobacteria Survival by Inhibiting the Expression of Inflammatory Mediators and Cell Apoptosis in Macrophages

“…MptpB is a critical virulence factor secreted by Mtb. Its structural information indicates that it belongs to the family of protein tyrosine phosphatase (He et al, 2015 ; Ghattas et al, 2016 ), whose protein conformation switches between “closed” and “open” forms to resist oxidative inactivation (Flynn et al, 2010 ). In vitro experiments showed that it has triple substrate specificity toward phosphortyrosine, phosphorserine/threonine, and phosphoinositides (Beresford et al, 2007 ), and its activity appears to be regulated by lysine acylation (Singhal et al, 2015 ).…”

High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

“…Additionally, phosphotyrosine (pTyr) residues play critical roles in substrate recognition, and replicating these interactions with pTyr mimetics often entails the inclusion of anionic moieties, which impede cell permeability and reduce bioavailability (Barr, 2010). Even so, there continues to be considerable interest in discovering novel therapeutic agents to target PTPs (Ghattas et al, 2016), and inhibitors of multiple PTPs are currently being developed (Stanford & Bottini, 2017).…”

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

“…Recent studies have demonstrated the improved drugability of the allosteric binding sites of PTP1B as compared to its catalytic/active site . Allosteric sites have higher specificity, novel modes of efficacy, lower toxicity, and fewer side effects compared to the evolutionarily conserved active sites .…”

“…Recently, Krishnan et al discovered that PTP1B could be inhibited allosterically by a small‐molecule inhibitor, MSI‐1436, through a novel mechanism that involves cooperative effects between a unique binding site located at the noncatalytic C‐terminal end of PTP1B (that lies between residues D367‐L394) and a second binding site located close to its catalytic segment (a site incorporating helix S285‐S295 and residues L299, H310, and I311) . MSI‐1436 has passed phase I clinical trials successfully but due to financial constraints, it did not advance to phase II trials …”

“…Studies conducted on PTP druggability suggest that the different conformations of PTP1B could also be exploited in inhibitor design . PTP1B can exist in “open” and “closed” conformations .…”