Binding mechanisms of varic acid inhibitors on protein tyrosine phosphatase 1B and in silico design of the novel derivatives

Protein Tyrosine Phosphatase 1B (PTP1B) has become a drug target for the treatment of type 2 diabetes. Unfortunately, there is no drugs PTP1B on market. Varic acid analogues are kind novel promising inhibitors. In this work, we used molecular docking, dynamics simulation, MM/GBSA binding free energy calculation to study mechanisms varic inhibitors and design derivatives lead validation. Our computation shows that common motif structure (2,4-dihydroxy-6-propylbenzoic acid) compounds 1, 4, 6 similar interactions with active site, while 3 5 have different characteristics. The decomposition indicates Tyr46, Ser216, Ala217, Ile219, Arg221, Gln262 more significant By analysing 35 PTP1B-ligand crystal structures, extracted key structural characteristics in ligand binding. Based these mechanism inhibitors, 17 were designed using compound as parent structure. Except rejected molecules PAINS predicted by ADMET evaluation, retained favourable than 6.