| Protein tyrosine phosphatase 1B（PTP1B）is one of the targets of type II diabetes.In order to obtain inhibitors against PTP1B from natural products,a library of natural products containing 42296 small molecules was constructed,and PTP1B protein（PDB code:1XBO）was selected as target.Virtual screening against the library was conducted to determine the occurrence of PTP1B inhibitors.The analysis of the binding mode of candidate inhibitors in the active site of PTP1B were carried out,and enzyme inhibition assay in vitro was also operated.Three good drug-like molecules,namely para-benzoquinone compound 42,isocoumarins derivative 45 and Clavepictine analogue 46,were identified by means of molecular docking simulation.Of which,the PTP1B inhibitory activity of compound 42 was reported before.Binding model analysis revealed that compound 42 is embedded into the first site and YRD loop,binding with the PTP1B by hydrogen bond interactions,van der Waals interactions,electrostatic interaction.Compound 45 can be stabilized by five hydrogen bonds,π-σbond,van der Waals contacts,electrostatic interaction,simultaneously occupying the first and the second site.Additionally,the binding force between 45 and WPD loop or linker also exists,These results support the hypothesis that 45 would have high affinity and selectivity on PTP1B.Seven hydrogen bonds are established between 46 and PTP1B,indicating that 46 mainly binds first site.Pharmacophore models were established to screen potential PTP1B inhibitors from natural products library,which were Hip Hop pharmacophore models,3D pharmacophore models,and Structure based pharmacophore models.Four good drug-like molecules,namely long-chain polyol fatty acids compounds 88 and 91,sialyl Lewis-x mimetics containing naphthyl backbones 140 and pleionin A analogue 147 were selected as possible inhibitors.Binding model analysis showed that,compound 88 can extend easily deep into the first site,forming hydrogen bond interactions with the PTP1B.Compound 91 is linked with PTP1B primarily by hydrogen bonds and electrostatic interactions,occupying the first site and YRD loop.Compound 140 was also observed to occupy the same site as 91,conjugated with PTP1B mainly by one hydrogen bonds and twoπ-σbonds.Compound 147 forms two hydrogen bonds and twoπ-σbonds with PTP1B,mainly occupying the first site.There also exist goodπ-πstacking interactions between 147 and YRD loop or WPD loop.The in vitro inhibition activity of isocoumarins derivative 45 on PTP1B enzyme was tested,and the IC50 of 45 is 74.58±1.24μmol/L.Besides,compound 45 was identified as a reversible inhibitor through the enzyme inhibition type test. |
