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Research Articles

Discovery of novel inhibitors for Pseudomonas aeruginosa lipase enzyme from in silico and in vitro studies

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 2197-2210 | Received 28 Dec 2022, Accepted 10 Apr 2023, Published online: 26 Apr 2023

Figures & data

Figure 1. (A) Hydrolysis of triglycerides. (B) Catalytic mechanism of lipolysis in Pseudomonas aeruginosa (adapted from Jegannathan et al., Citation2008 and Röttig et al., Citation2010).

Figure 1. (A) Hydrolysis of triglycerides. (B) Catalytic mechanism of lipolysis in Pseudomonas aeruginosa (adapted from Jegannathan et al., Citation2008 and Röttig et al., Citation2010).

Table 1. Docking score values and free energies of binding (MMGBSA) for each compound, obtained from the virtual screening.

Figure 2. The structure of Pseudomonas aeruginosa lipase with the catalytic triad in stick model and the four alpha-helices of the cap domain indicated in yellow.

Figure 2. The structure of Pseudomonas aeruginosa lipase with the catalytic triad in stick model and the four alpha-helices of the cap domain indicated in yellow.

Figure 3. Chemical structures of Bromhexine and the compounds identified in this work.

Figure 3. Chemical structures of Bromhexine and the compounds identified in this work.

Figure 5. Root-mean-square deviation (RMSD) values for the 11 hits and the reference compound during one of the 200 ns MD simulations. (A) RMSD values for the 4 best hit compounds N1-N4, (B) RMSD values for the 7 hit compounds N5-N11, (C) Root mean square fluctuations (RMSF) of the lipase protein during the 200 ns MD simulations in complex with Bromhexine or ligands N1-N4. Red arrows correspond to the location of catalytic residues. Black arrows indicate which parts of the protein that undergoes more movements during the simulation (see text for details).

Figure 5. Root-mean-square deviation (RMSD) values for the 11 hits and the reference compound during one of the 200 ns MD simulations. (A) RMSD values for the 4 best hit compounds N1-N4, (B) RMSD values for the 7 hit compounds N5-N11, (C) Root mean square fluctuations (RMSF) of the lipase protein during the 200 ns MD simulations in complex with Bromhexine or ligands N1-N4. Red arrows correspond to the location of catalytic residues. Black arrows indicate which parts of the protein that undergoes more movements during the simulation (see text for details).

Table 2. 50% inhibition concentration of the lipase inhibitors.

Figure 6. Structural changes in the lipase protein. (A) Lipase structure (PDB ID 1EX9) containing phosphonate trioctyl as ligand. (B) Lipase structure containing Bromhexine after 200 ns MD simulation. The changes in the conformation of the key α-helix is indicated with the dashed circle.

Figure 6. Structural changes in the lipase protein. (A) Lipase structure (PDB ID 1EX9) containing phosphonate trioctyl as ligand. (B) Lipase structure containing Bromhexine after 200 ns MD simulation. The changes in the conformation of the key α-helix is indicated with the dashed circle.

Figure 7. Graph of hydrogen bonds for Bromhexine and compounds N1-N4 during a 200 ns MD simulation.

Figure 7. Graph of hydrogen bonds for Bromhexine and compounds N1-N4 during a 200 ns MD simulation.

Figure 8. Graph of RMSD estimate averaged over 10 BPMD trials for Bromhexine and compounds N1-N4 binding to Lipase, vs simulation time.

Figure 8. Graph of RMSD estimate averaged over 10 BPMD trials for Bromhexine and compounds N1-N4 binding to Lipase, vs simulation time.
Supplemental material

Supplemental Material

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Data availability

All docked structures, MD simulation trajectories, and BPMD data are available as free download from Zenodo.org, DOI: 10.5281/zenodo.7003747.