Structure-based Identification of Endocrine Disrupting Pesticides Targeting Breast Cancer Proteins

Abstract

Endocrine disrupting pesticides (EDPs) are exogenous compounds that disrupt endocrine activity. Human exposure to EDPs can occur through occupational contact, and through the consumption of food, milk and water with trace amounts of these pollutants. Several EDPs are epidemiologically linked to breast cancer or are considered as possible carcinogens. However, current evidence is not fully conclusive and their mechanisms of action remain unknown. Thus, the potential interactions between 262 EDPs and 189 proteins associated with breast cancer were evaluated by using a virtual high-throughput screening approach, with AutoDock Vina 1.1.1. The molecular coordinates were previously downloaded from Protein Data Bank and EDCs DataBank, and used for preparation and optimization in Sybyl X-2.0. The best affinity score (-11.0 kcal/mol) was obtained for flucythrinate with the nuclear receptor for vitamin D (VDR). This synthetic pyrethroid, along with other EDPs, such as fluvalinate, bifenthrin, cyhalothrin and cypermethrin, are proposed as multi-target ligands of several proteins related to breast cancer. In addition, the validation of our protocol showed a good accuracy in terms of binding pose prediction and affinity estimation. This study provides a guide to prioritize EDPs for which further in vitro and in vivo analysis could be done to evaluate the risk and possible mechanisms of action of these contaminants and their potential association with breast cancer.

Keywords: Virtual screening; biocide; endocrine disruptor; molecular docking; plant protection product; pyrethroid.