Computational insight into the selective allosteric inhibition for PTP1B versus TCPTP: a molecular modelling study

Abstract

All over the world, diabetes mellitus type 2 has spread as a problematic pandemic. Despite currently available treatments, approved drugs still show undesirable side effects and loss of efficacy or target symptoms instead of causes. Protein tyrosine phosphatase 1B (PTP1B), since its discovery, has emerged as a very promising target against this disease. Although the information regarding the enzyme is immense, little is known about the selectivity between this enzyme and its closest homologue, lymphocyte T tyrosine phosphatase (TCPTP), which is responsible for complicated side effects. In this study, on the basis of different computational approaches, we are able to highlight the importance of a phenylalanine residue located in PTP1B, but not in TCPTP, as a crucial hotspot that causes selectivity and stability for the whole ligand bound system. These results not only allow to explain the selectivity determinants of PTP1B but also provide a useful guide for the design of new allosteric inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Diabetes mellitus
• PTP1B
• TCPTP
• molecular dynamics

Acknowledgements

Author is grateful to Ramón Alajarín for its fruitful and invaluable conversation and manuscript supervision and J. J. Vaquero for its guidance. The author would like to thank Enago (www.enago.com) for the English language review. Author acknowledges Águeda Molinero-Fernández by its help with statistical analysis. Author is grateful to the anonymous reviewers for helpful suggestions.

Disclosure statement

Author declared the is not any conflict of interest to publish this manuscript in Journal of Biomolecular Structure and Dynamics.

Additional information

Funding

This work was supported by Ministerio de Economía y Competitividad (CTQ2017-85263-R) and Instituto de Salud Carlos III/REDinRED (RD16/0009/0015). Author is grateful for the Fellowships provided by University of Alcala and Ministerio de Educación Cultura y Deporte (FPU16/01647).