%0 Journal Article
%T Discovery of YopE Inhibitors by Pharmacophore-Based Virtual Screening and Docking
%A Gizem Ozbuyukkaya
%A Elif Ozkirimli Olmez
%A Kutlu O. Ulgen
%J ISRN Bioinformatics
%D 2013
%R 10.1155/2013/640518
%X 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. 1. Introduction The Rho family of small (20¨C40£¿kDa) GTPases, which are monomeric G-proteins, belong to the Ras superfamily of GTPases containing more than 150 proteins [1]. The Ras superfamily has been classified into 5 subfamilies based on their sequence similarity which are Ras, Rho, Rab, Ran, and Arf [1, 2]. The Rho family of GTPases are cell membrane-associated GTP-binding proteins that actively participate in cell signaling networks, which regulate actin organization, cell cycle progression and gene expression [3, 4]. Up to date, 20 members of Rho GTPases have been found in four main subclasses, namely, Rho, Rnd, Rac, and Cdc42 [2, 5]. Rho GTPases are the most fundamental regulators of the actin cytoskeleton, along with other crucial properties in the cell, such as cell adhesion, gene transcription and cell proliferation, cell motility, vesicular trafficking, phagocytosis, and cytokinesis [2, 4¨C9]. Similar to other G-proteins and GTPases, Rho family proteins can serve as molecular switches, by binding to either GDP or GTP. GTPases are active and are capable of transmitting cell signals to downstream proteins when they are bound to GTP and inactive when they are bound to GDP [10, 11]. 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
%U http://www.hindawi.com/journals/isrn.bioinformatics/2013/640518/