Abstract: As a kind of potential drug for treating the Type II diabetes, the inhibitor of protein tyrosine phosphatase 1B (PTP1B) is an important research field, in which a kind of bidentate inhibitors is the research focus. In this paper, molecular dynamics simulation and MM/GBSA method were employed to calculate the binding free energy of the protein-ligand complexes. The rank of the predicted free energies of the complexes is well consistent with the experiment data. The energy decomposition analysis based on the MM/GBSA also indicates the importance of second binding site, especially the residue ARG24 and ARG254 of PTP1B, in producing selectivity against SHP-2, but not so high selectivity against TCPTP. Also the inhibitor has important interaction with the residue of PHE182 of PTP1B, this is another reason that produces the selectivity against TCPTP. We expect that the information obtained in this work can help to develop potential PTP1B inhibitors with more promising specificity.

Key words: protein tyrosine phosphatase 1B, molecular dynamics simulations, free energy calculations, free energy decomposition analysis, MM/GBSA