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Identification of New Potential Inhibitors of Quorum Sensing through a Specialized Multi-Level Computational Approach
Authors:Fbio G Martins  Andr Melo  Srgio F Sousa
Institution:1.UCIBIO/REQUIMTE, BioSIM—Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;2.LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, 4169-007 Porto, Portugal;
Abstract:Biofilms are aggregates of microorganisms anchored to a surface and embedded in a self-produced matrix of extracellular polymeric substances and have been associated with 80% of all bacterial infections in humans. Because bacteria in biofilms are less amenable to antibiotic treatment, biofilms have been associated with developing antibiotic resistance, a problem that urges developing new therapeutic options and approaches. Interfering with quorum-sensing (QS), an important process of cell-to-cell communication by bacteria in biofilms is a promising strategy to inhibit biofilm formation and development. Here we describe and apply an in silico computational protocol for identifying novel potential inhibitors of quorum-sensing, using CviR—the quorum-sensing receptor from Chromobacterium violaceum—as a model target. This in silico approach combines protein-ligand docking (with 7 different docking programs/scoring functions), receptor-based virtual screening, molecular dynamic simulations, and free energy calculations. Particular emphasis was dedicated to optimizing the discrimination ability between active/inactive molecules in virtual screening tests using a target-specific training set. Overall, the optimized protocol was used to evaluate 66,461 molecules, including those on the ZINC/FDA-Approved database and to the Mu.Ta.Lig Virtual Chemotheca. Multiple promising compounds were identified, yielding good prospects for future experimental validation and for drug repurposing towards QS inhibition.
Keywords:biofilms  Chromobacterium violaceum  CviR  quorum-sensing  virtual screening  molecular docking  molecular dynamics simulations  MM/PBSA  MM/GBSA
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