In silico evaluation of pesticides as potential modulators of human DNA methyltransferases

DNA methylations are carried out by DNA methyltransferases (DNMTs) that are key enzymes during gene expression. Many chemicals, including pesticides, have shown modulation of epigenetic functions by inhibiting DNMTs. In this work, human DNMTs were evaluated as a potential target for pesticides through virtual screening of 1038 pesticides on DNMT1 (3SWR) and DNMT3A (2QRV). Molecular docking calculations for DNMTs-pesticide complexes were performed using AutoDock Vina. Binding-affinity values and contact patterns were employed as selection criteria of pesticides as virtual hits for DNMTs. The best three DNMT-pesticides complexes selected according to their high absolute affinity values (kcal/mol), for both DNMT1 and DNMT3A, were flocoumafen (−12.5; −9.9), brodifacoum (−12.4; −8.4) and difenacoum (−12.1; −8.7). These chemicals belong to second-generation rodenticides. The most frequent predicted interacting residues for DNMT1-pesticide complexes were Trp1170A, Phe1145A, Asn1578A, Arg1574A and Pro1225A; whereas for DNMT3A those were Arg271B, Lys740A, and Glu303B. These results suggest that rodenticides used for pest control are potential DNMT ligands and therefore, may modulate DNA methylations. This finding has important environmental and clinical implications, as epigenetic pathways are critical in many biochemical processes leading to diseases.