Design of specific inhibitors of the protein tyrosine phosphatase SHP-2 by virtual screening and core hopping method

Abstract

The protein tyrosine phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is an important signalling component of growth factors, cytokines and oncogenic bacteria. Studies have identified that gain-of-function SHP-2 mutations were associated with the Noonan syndrome, various kinds of leukaemias and solid tumours. However, it is complicated to find the specific inhibitors for SHP-2 over the closely related tyrosine phosphatase SHP-1 and protein tyrosine phosphatase 1B (PTP1B). The aim of this study was to develop potent and specific SHP-2 inhibitors as anticancer and antileukaemia agents. So the ZINC fragment database was searched for finding the optimal compound with the core hopping technique. As a result, the 15 compounds were obtained. It was observed by molecular dynamics simulations that those compounds interact with the active site of SHP-2 more strongly than with the corresponding sites of the closely related protein tyrosine phosphatases, SHP-1 and PTP1B. The ‘absorption, distribution, metabolism and excretion’ prediction shows that the 15 compounds may become candidates for developing powerful and novel drugs for treating Noonan syndrome, juvenile myelomonocytic leukaemia and possibly other SHP-2-associated cancers.