In silico identification of novel PqsD inhibitors: promising molecules for quorum sensing interference in Pseudomonas aeruginosa

Abstract

PqsD is an anthraniloyl-CoA anthraniloyltransferase involved in the synthesis of the secondary metabolites essential to the formation of Pseudomonas quinolone signal (PQS) inducer molecules. Its main substrate is anthraniloyl-coenzyme A (ACoA) but it can accept malonyl-CoA as secondary substrate. Suppression of PqsD activity has been connected to the inhibition of biofilm formation and can also be a good target for dual inhibition, when combined with PqsR inhibition. Here we describe the validation and application of an in silico methodology to find new compounds to inhibit PqsD. Using molecular docking and structure-based virtual screening protocols, five databases of compounds were screened (FDA approved subset of the ZINC database, Chimiothèque Nationale, Mu.Ta.Lig. Virtual Chemotheca, Interbioscreen (IBS), and Comprehensive Marine Natural Products Database (CMNPD)), representing a total of 221 146 molecules. The top five compounds of each database were selected to be further analysed using molecular dynamics simulations. Binding affinity was validated using free energy calculations, enabling the selection and characterization of eight compounds for future studies aiming to develop new quorum sensing inhibitors.