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

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.