Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling. Therefore, PTP1B is an attractive target to design new drugs against Type 2 diabetes. Our research group previously report a benzimidazole derivative that inhibits PTP1B (compound 1). Due to its Ki value in the low micromolar range (4.2 µmol) and drug like properties, it was selected for optimization. With the aim to design more potent and selective inhibitors, a computer-aided ligand-based strategy was applied. To this end, a detailed analysis of the interactions PTB1B-compund 1 was performed by molecular docking using Extra Precision and Induced Fit tools in Glide program from Maestro software (www.shrodinger.com). Additionally, in view of the high structural similarity among the catalytic domain of PTP1B and its closest homologous T-cell-PTP (TCPTP), the interactions showed by the selective inhibitors reported were taking into account also. This information was used to propose a series of 30 new compound 1 derivatives, modifying substituents at positions 2, 5 and 6 in the benzimidazole core. These compounds were docked into PTP1B and TCPTP catalytic sites. The data shoed that compounds denominated MCα-1, MCα-2, MCβ-1 and ISα presented the best interactions to account for selectivity. These molecules were selected for synthesis and their inhibitory effect in PTP1B and TCPTP was evaluated. The results indicated that the compounds were able to inhibit PTP1B and their activity against TCPTP is being tested. Therefore, these molecules can be used to continue the optimization process in the search of more potent and selective PTP1B inhibitors.

Design through computer-aided approach and synthesis of new benzimidazole derivatives as inhibitors of protein tyrosine phosphatase 1B

2019 Fall National Meeting

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