Unveiling the potential of recently FDA-approved drugs as quorum sensing inhibitors against P. Aeruginosa using high-performance computational techniques

Abstract

Through cell-to-cell communication, activation of efflux pumps, formation of biofilms, and other mechanisms, pseudomonas aeruginosa’s quorum sensing systems (QSS), notably the lasl/las-r system, contribute a vital role in the development of anti-microbial resistance (AMR). Identifying potential drugs against these targets could have significant implications for combating pseudomonal infections. The current study aims to identify promising recently FDA-approved drugs against lasl/las-r proteins. The ligands were selected from the FDA-approved drug lists of the last 5 years. Out of 202, 78 drugs were checked for interaction with lasl/las-r protein and 4 drugs revealed top binding conformations characterized by favorable energetic profiles within the active site of the las-r protein which were further assigned for 250-ns molecular dynamics (MD) simulation. The MD analysis confirmed the dynamical stability of brexanolone and oteseconazole with las-r protein. The root mean square deviation (RMSD), radius of gyration (Rg) and solvent-accessible surface area (SASA) analysis have indicated less deviation, more compactness of protein and less exposure of protein ligand complex to its surroundings as compared to the reference ligand-protein complex. The hydroxyl group in the oteseconazole whereas hydroxyl and ketone group in the brexanolone were responsible for hydrogen bonds with the active site residue of las r ptotein as indicated by ligand-protein contacts diagram. The binding energies per residue analysis revealed TYR-47 as the most contributing amino acid residue for interaction with oteseconazole and brexanolone. The identified drugs may be potential repurposing candidates against pseudomonal infections through inhibition of las-r protein.

Communicated by Ramaswamy H. Sarma

Keywords:

• US-FDA approved drugs
• quorum sensing
• repurposing
• molecular docking
• molecular dynamics
• MM-gbsa

Acknowledgments

The authors are thankful to DST SERB SRG (SRG/2022/000011) for providing necessary facilities to carry out this work.

Disclosure statement

No potential conflict of interest was reported by the author(s)

Additional information

Funding

The work was funded by Department of Science and Technology, Science and Engineering Research Board (DST-SERB), Govt of India as a DST SERB SRG Project [SRG/2022/000011].