Inhibition of glutathione S-transferases by calix[4]arene-based phosphinic acids

Abstract

Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against GST from equine liver and human recombinant GSTA1-1, while being selective over the enzyme from human placenta and GSTP1-1. The thiacalix[4]arene phosphinic acid was the most active inhibitor of equine liver GST and GSTA1-1 with IC50 values of 85 nM and 50 nM, respectively. Kinetic studies revealed that the inhibition was of non-competitive type concerning both enzyme substrates, glutathione, and 1-chloro-2,4-dinitrobenzene. Molecular docking was carried out to predict possible binding sites for thiacalix[4]arene-based phosphinic acid on the surface of homodimeric GSTA1-1

Identification of Potential Drug Targets of Calix[4]arene by Reverse Docking

“…In this case, the smallest calix [4]arene represents the ideal scaffold to develop inhibitors, due to its rigidity that strongly reduces the entropic penalty typical of every binding process. Calixarene derivatives are efficient inhibitors of alkaline phosphatase, [34][35][36] ion channels, [37] histone deacetylase, [38] galectin-1, [39,40] glutathione-S-transferase, [41,42] tyrosine phosphatase, [43][44][45][46] HIV-1 integrase, [47,48] HIV protease, [49] protein disulfide isomerase, [50] AXL tyrosine kinase receptor, [51] HIV-1 nucleocapsid protein, [52] α-mannosidase, [53] bromelain and polyphenol oxidase, [54] and carbonic anhydrase. [55] Over the last twenty years, a substantial amount of work was carried out to study the interaction of calixarene derivatives with biomolecules, in particular to identify their interactions with druggable proteins.…”