Rational Drug Design for Pseudomonas aeruginosa PqsA Enzyme: An in silico Guided Study to Block Biofilm Formation

Frontiers in Molecular Biosciences
Bilal ShakerDokyun Na

Abstract

Pseudomonas aeruginosa is an opportunistic gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Such infections occur owing to biofilm formation that confers multidrug resistance and enhanced pathogenesis to the bacterium. In this study, we used a rational drug design strategy to inhibit the quorum signaling system of P. aeruginosa by designing potent inhibitory lead molecules against anthranilate-CoA ligase enzyme encoded by the pqsA gene. This enzyme produces autoinducers for cell-to-cell communication, which result in biofilm formation, and thus plays a pivotal role in the virulence of P. aeruginosa. A library of potential drug molecules was prepared by performing ligand-based screening using an available set of enzyme inhibitors. Subsequently, structure-based virtual screening was performed to identify compounds showing the best binding conformation with the target enzyme and forming a stable complex. The two hit compounds interact with the binding site of the enzyme through multiple short-range hydrophilic and hydrophobic interactions. Molecular dynamic simulation and MM-PBSA/GBSA results to calculate the affinity and stability of the hit compounds with the...Continue Reading

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May 6, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fábio G MartinsSérgio F Sousa
Aug 31, 2021·Frontiers in Molecular Biosciences·Edward KingRay Luo

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