Determination of the binding affinities of OPEs to integrin αvβ3 and elucidation of the underlying mechanisms via a competitive binding assay, pharmacophore modeling, molecular docking and QSAR modeling

Abstract

Organophosphate esters (OPEs) can cause adverse biological effects through binding to integrin α_vβ₃. However, few studies have focused on the binding activity and mechanism of OPEs to integrin α_vβ₃. Herein, a comprehensive investigation of the mechanisms by which OPEs bind to integrin α_vβ₃ and determination of the binding affinity were conducted by in vitro and in silico approaches: competitive binding assay as well as pharmacophore, molecular docking and QSAR modeling. The results showed that all 18 OPEs exhibited binding activities to integrin α_vβ₃; moreover, hydrogen bonds were identified as crucial intermolecular interactions. In addition, essential factors, including the -P = O structure of OPEs, key amino acid residues and suitable cavity volume of integrin α_vβ₃, were identified to contribute to the formation of hydrogen bonds. Moreover, aryl-OPEs exhibited a lower binding activity with integrin α_vβ₃ than halogenated- and alkyl-OPEs. Ultimately, the QSAR model constructed in this study was effectively used to predict the binding affinity of OPEs to integrin α_vβ₃, and the results suggest that some OPEs might pose potential risks in aquatic environments. The results of this study comprehensively elucidated the binding mechanism of OPEs to integrin α_vβ₃, and supported the environmental risk management of these emerging pollutants.

Keywords: In vitro; Integrin α(v)β(3); Molecular docking; OPEs; QSAR.