Identification of potential Tpx inhibitors against pathogen-host interactions |
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| Affiliation: | 1. School of Material Sciences and Engineering, Hebei University of Technology, Tianjin 300130, PR China;2. Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100080, PR China;3. Condensed Matter and Sustainable Development Laboratory, Physics Department, University of Sidi-Bel-Abbès, 22000 Sidi-Bel-Abbès, Algeria;4. Department of Materials Science and Engineering, The University of Tennessee, Knoxville, TN 37996, USA;1. Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan;2. Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjyuku, Shinjyuku, Tokyo, Tokyo, 160-8402, Japan;1. School of Chemistry, Physics and Mechanical Engineering, Science and Engineering Faculty, Queensland University of Technology, GPO Box 2434, Brisbane, Queensland 4001, Australia;2. Geology Department, School of Mines, Federal University of Ouro Preto, Campus Morro do Cruzeiro, Ouro Preto, MG 35,400-00, Brazil;3. Federal University of Itajubá, Campus Itabira, Itabira, MG 35,903-087, Brazil;1. College of Computer and Information Science, Southwest University, Chongqing 400715, China;2. School of Mathematics and Statistics, The University of Sydney, New South Wales, Australia;1. Department of Materials Science and Engineering, Ghent University, Technologiepark 903, B-9052 Zwijnaarde, Ghent, Belgium;2. Department of Materials Engineering, KU Leuven, Kasteelpark Arenberg 44 (box 2450), B-3001 Leuven, Belgium |
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| Abstract: | Yersinia organisms cause many infectious diseases by invading human cells and delivering their virulence factors via the type three secretion system (T3SS). One alternative strategy in the fight against these pathogenic organisms is to interfere with their T3SS. Previous studies demonstrated that thiol peroxidase, Tpx is functional in the assembly of T3SS and its inhibition by salicylidene acylhydrazides prevents the secretion of pathogenic effectors. In this study, the aim was to identify potential inhibitors of Tpx using an integrated approach starting with high throughput virtual screening and ending with molecular dynamics simulations of selected ligands. Virtual screening of ZINC database of 500,000 compounds via ligand-based and structure-based pharmacophore models retrieved 10,000 hits. The structure-based pharmacophore model was validated using high-throughput virtual screening (HTVS). After multistep docking (SP and XP), common scaffolds were used to find common substructures and the ligand binding poses were optimized using induced fit docking. The stability of the protein–ligand complex was examined with molecular dynamics simulations and the binding free energy of the complex was calculated. As a final outcome eight compounds with different chemotypes were proposed as potential inhibitors for Tpx. The eight ligands identified by a detailed virtual screening protocol can serve as leads in future drug design efforts against the destructive actions of pathogenic bacteria. |
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| Keywords: | Tpx Virtual screening Molecular docking Efficiency index Substructure search |
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