DOI: https://doi.org/10.24959/ophcj.18.947

The assessment of sulfonylcalix[4]arene derivatives as inhibitors of protein tyrosine phosphatases

V. M. Buldenko, V. V. Trush, O. L. Kobzar, A. B. Drapailo, S. G. Vyshnevsky, V. I. Kalchenko, A. I. Vovk

Abstract


Aim. To compare sulfonylcalix[4]arene derivatives containing ionizable or non-ionizable substituents at the upper rim of the macrocycle as inhibitors of protein tyrosine phosphatase 1B (PTP1B) and other PTPs.
Results and discussion. The properties of sulfonylcalix[4]arene with four phosphonic acid groups introduced at the upper rim were compared with those of the macrocycles containing four non-ionizable tert-butyl or trifluoroacetamide functions. The sulfonylcalix[4]arene tetrakis-methylphosphonic acid was found to inhibit PTP1B with IC50 value in the low-micromolar range without selectivity over other PTPs, such as TC-PTP, MEG1, MEG2, SHP2, and PTPβ. At the same time, modification of sulfonylcalix[4]arene with trifluoroacetamide substituents led to inhibition of PTP1B with IC50 of 1.4 μM and 4- to 28 fold selectivity over the other PTPs. In order to understand the ability of inhibiting PTP1B by sulfonylcalix[4]arene with introduced trifluoroacetamide groups the molecular docking and molecular dynamic simulations were performed. The inhibition mechanism was discussed.
Experimental part. The activities of the test compounds in vitro were examined spectrophotometrically measuring the rate of hydrolysis of p-nitrophenyl phosphate as a substrate of PTPs. The molecular docking was performed by AutoDock Vina.
Conclusions. This study can start an approach to develop new inhibitors of PTPs by variations in the nonionogenic substituents on the upper rim of sulfonylcalix[4]arene scaffold.


Keywords


sulfonylcalix[4]arene; protein tyrosine phosphatase; inhibition; molecular docking; molecular dynamics

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