Energy-optimized pharmacophore coupled virtual screening in the discovery of quorum sensing inhibitors of LasR protein of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Therefore, attenuation of virulence by QS inhibition could be an alternative and effective approach to control the infections. In this study, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. The e-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs based on their higher binding affinity to LasR receptor (−7.53 to −10.32 kcal/mol compared to −7.43 kcal/mol of native ligand). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed stable binding affinity and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections.

Communicated by Ramaswamy H. Sarma

Keywords:

• Pseudomonas aeruginosa
• quorum sensing
• virtual screening
• e-pharmacophore
• drug discovery

Disclosure statement

The authors declare no conflict of interest.

Authors contribution

ZN designed and executed the computational works; ZN, SBS, and MAI performed the molecular docking; ZN, UKA, and MMK contributed in writing and critical revision of the manuscript; UKA supervised the whole work. All authors approved the final version of the manuscript for journal submission.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.