期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 181, 期 -, 页码 1171-1182出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2021.04.061
关键词
Pyrazoles; Protein tyrosine phosphatase 1B; Synthetic inhibitors; T-cell protein tyrosine phosphatase; Insulin signaling; Insulin resistance; Diabetes
资金
- FCT/MCTES [UIDB/50006/2020, UID/DTP/04138/2020, PTDC/MED-QUI/29241/2017 -POCI-01-0145-FEDER-029241]
- FCT/MCTES through Programa Operacional Competitividade e Internacionalizacao (COMPETE)
- Fundacao para a Ciencia e a Tecnologia (FCT) through the PhD Programme in Medicines and Pharmaceutical Innovation (i3DU) [PD/BD/145169/2019]
- European Union [FEDER funds through the Operational Competitiveness Program (COMPETE)] [POCI-01-0145-FEDER-029248]
- [POCI-01-0145-FEDER-029241]
- Fundação para a Ciência e a Tecnologia [PD/BD/145169/2019] Funding Source: FCT
This study evaluated a library of 22 pyrazole compounds against human PTP1B activity, identifying two potent inhibitors and highlighting the importance of additional benzene rings in enhancing PTP1B inhibition. The most active compounds showed selectivity over TCPTP and molecular docking analyses revealed key residue contacts. This study represents a significant step in the design of novel PTP1B inhibitors.
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]}-1phenylpyrazole 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. (c) 2021 Elsevier B.V. All rights reserved.
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