In silico study of organophosphorus pesticides' ability to bind to the ABCG2 transporter in the context of health risks associated with breastfeeding.

Introduction

ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter responsible for pumping compounds out of cells. It influences systemic exposure and pharmacokinetics of compounds by reducing their absorption in the gastro-intestinal tract and regulating tissue distribution and excretion. The ABCG2 protein is responsible for the detoxification of tissues, but also for multi-drug resistance in cancer therapies. One of the possible routes for the excretion of compounds facilitated by ABCG2 is via mother’s milk, so the binding of compounds to this transporter may be a risk factor during breastfeeding. In this study, organophosphorus pesticides were analyzed in the context of their ability to reach mother’s milk by facilitated rather than passive diffusion, using the ABCG2 transport protein.

Material and Method

A total of 18 organophosphorus pesticides were subjected to molecular docking using the AutoDock Vina method. The 3D cryo-electron microscopy structure of the ABCG2 transporter bound to a ligand denoted as BWQ (PDB code: 6FFC) was obtained from the RCSB Protein Data Bank as a template for in silico calculations. The structure of the target protein was prepared by removing heteroatoms, crystallographic water and ions. The dimensions of a docking grid box were 30 Å x 30 Å x 30 Å, and the center coordinates were 131, 127 and 145 (x, y and z, respectively).

Results

It was established that the organophosphorus pesticides exhibit relatively strong affinities for the studied transporter (ca. -7 to -10 kcal/mol) and the protein–ligand interactions occur mainly by hydrogen bonds, carbon–hydrogen bonds, π–π stacking or van der Waals forces. The main aminoacid residues responsible for the binding of each pesticide to the target protein were identified.

Conclusions

Based on the results of in silico calculations, it may be concluded that the studied pesticides are likely to reach mother’s milk by facilitated diffusion or mixed mechanisms. Further studies of the stability of protein–pesticide complexes are underway.