Pharmacophore design and ensemble-docking as approach to screening a large-scale database for identification of potential inhibitors of APH(3')-IIIa of Enterococcus faecalis

Fighting nosocomial infections represents one of the main difficulties in medical treatment units around the world. Among the bacteria with the greatest potential to cause these complications is Enterococcus faecalis, mainly due to the expression of aminoglycoside-modifying enzymes. In the approach adopted in this work, pharmacophore modeling followed by ensemble-docking were carried out to select potential inhibitors against the nucleotide binding site of EfAPH(3')-IIIa. The most promising ligands are all nucleotide analogues (ZINC000828691112, ZINC000029546074 and ZINC000062624753) and showed good toxicological and pharmacokinetic profiles and the ability to interact with key amino acids such as MET26, SER27 and TYR42. Taken together, these preliminary results show that nucleotide analogues may represent a promising structure for interacting with the EfAPH(3')-IIIa nucleotide-binding pocket. Further analysis will be conducted.