Prediction of potential inhibitors against Yersinia YopE and Salmonella SopE by virtual screening and docking

Abstract

Outer proteins of gram negative bacteria Yersinia and Salmonella secrete virulence factors that invade eukaryotic cells via type III secretion system. Yersinia outer protein E, YopE, and Salmonella outer protein E, SopE, are cytotoxic and pathogenic for humans, and they target small GTPases of Rho family. Rho family of GTPases acts as molecular switches in many cell signaling pathways that affect actin skeleton arrangement, cell motility and apoptosis. Interaction of YopE or SopE with Rho GTPases induces cytoskeletal disruption and depolymerisation of actin stress fibers within the cell, and can lead to many diseases, including cancer. In this work, to the aim was to discover novel inhibitors that would block biological functioning of the bacterial pathogen Salmonella SopE and Yersinia YopE, with the help of computational drug design tools. To this end, small molecule database formation, 3D database screening with pharmacophore building, molecular docking and scoring were carried out to propose a set of biologically active YopE and SopE inhibitors. For target YopE, quantitative structure-activity relationship (QSAR) method was incorporated into ligand-based pharmacophore building; whereas structure-based pharmacophores were constructed for target SopE. 3D pharmacophore models were constructed, and database generated from ZINC containing 25 million conformers was pre-filtered using the selected models. Molecular docking of filtered compounds was carried out with Schrödinger software Glide, taking ligand flexibility into account. The accuracy of each docking was presented with GlideScore and ranked accordingly. Top ranking results were further analyzed according to their interactions with target, druglikeness and bioavailability. Ultimately, a total of ten molecules were proposed as potent inhibitors against YopE and SopE, among which Y1 (ZINC02736077) and S1 (ZINC00370772) showed the highest predicted binding affinity towards YopE and SopE, respectively.