Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors: An in vitro and in silico study

• Published in: International journal of biological macromolecules 2021-06, Vol.181, p.1171-1182
• Main Authors: Rocha, Sónia, Lucas, Mariana, Silva, Vera L.M., Gomes, Pedro M.O., Silva, Artur M.S., Araújo, Alberto N., Aniceto, Natália, Guedes, Rita C., Corvo, M. Luísa, Fernandes, Eduarda, Freitas, Marisa
• Format: Article
• Language: English
• Subjects: Diabetes; Insulin resistance; Insulin signaling; Protein tyrosine phosphatase 1B; Pyrazoles; Synthetic inhibitors; T-cell protein tyrosine phosphatase
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2021.04.061

Type 2 diabetes mellitus (DM) is a complex chronic disorder and a major global health problem. Insulin resistance is the primary detectable abnormality and the main characteristic feature in individuals with type 2 DM. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which dephosphorylates insulin receptor and insulin receptor substrates, suppressing the insulin signaling cascade. Therefore, the inhibition of PTP1B has become a potential strategy in the management of type 2 DM. In this study, a library of 22 pyrazoles was evaluated here for the first time against human PTP1B activity, using a microanalysis screening system. The results showed that 5-(2-hydroxyphenyl)-3-{2-[3-(4-nitrophenyl)-1,2,3,4-tetrahydronaphthyl]}-1-phenylpyrazole 20 and 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 22 excelled as the most potent inhibitors of PTP1B, through noncompetitive inhibition mechanism. These findings suggest that the presence of additional benzene rings as functional groups in the pyrazole moiety increases the ability of pyrazoles to inhibit PTP1B. The most active compounds showed selectivity over the homologous T-cell protein tyrosine phosphatase (TCPTP). Molecular docking analyses were performed and revealed a particular contact signature involving residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. This study represents a significant beginning for the design of novel PTP1B inhibitors. [Display omitted] •Protein tyrosine phosphatase 1B (PTP1B) regulates the insulin signaling pathway.•PTP1B inhibition is currently a recognized promising target in type 2 diabetes.•Pyrazoles were shown to be effective inhibitors of PTP1B.•Molecular docking analysis revealed a particular contact signature of pyrazoles.