Abstract
Gram-negative bacteria Yersinia secrete virulence factors that invade eukaryotic cells via type III secretion system. One particular virulence member, Yersinia outer protein E (YopE), targets Rho family of small GTPases by mimicking regulator GAP protein activity, and its secretion mainly induces cytoskeletal disruption and depolymerization of actin stress fibers within the host cell. In this work, potent drug-like inhibitors of YopE are investigated with virtual screening approaches. More than 500,000 unique small molecules from ZINC database were screened with a five-point pharmacophore, comprising three hydrogen acceptors, one hydrogen donor, and one ring, and derived from different salicylidene acylhydrazides. Binding modes and features of these molecules were investigated with a multistep molecular docking approach using Glide software. Virtual screening hits were further analyzed based on their docking score, chemical similarity, pharmacokinetic properties, and the key Arg144 interaction along with other active site residue interactions with the receptor. As a final outcome, a diverse set of ligands with inhibitory potential were proposed.
Highlights
The Rho family of small (20–40 kDa) GTPases, which are monomeric G-proteins, belong to the Ras superfamily of GTPases containing more than 150 proteins [1]
guanine nucleotide exchange factors (GEFs) stimulate the substitution of GDP for GTP to activate Rho GTPases, whereas GTPase-activating proteins (GAPs) inactivate Rho GTPases by stimulating the substitution of GTP for GDP
Pharmacophore modeling and screening, and molecular docking and scoring were carried out to propose a set of biochemically active molecules with inhibition potential against Yersinia outer protein E (YopE)
Summary
The Rho family of small (20–40 kDa) GTPases, which are monomeric G-proteins, belong to the Ras superfamily of GTPases containing more than 150 proteins [1]. The Rho family of GTPases are cell membraneassociated GTP-binding proteins that actively participate in cell signaling networks, which regulate actin organization, cell cycle progression and gene expression [3, 4]. Since nucleotide association and dissociation are normally slow, some regulators within the cell catalyze the process of cycling between GDP- and GTP-bound states of Rho GTPases [12, 13]. These regulators are guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs) [14]. Nucleotide exchange occurs due to the conformational changes in Switch I and Switch II regions of GTPases, upon their contact with GEFs/GAPs [5, 11]
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