In Silico Docking of Traditional Chinese Medicine Compounds and Novel Redesigned Ligands to Pseudomonas aeruginosa Quinolone Signaling Proteins PqsA and PqsD

Abstract

Pseudomonas aeruginosa is a gram-negative bacterium that can survive a wide range of natural environments. Its growing resistance to antibacterial drugs is due to quorum sensing, specifically via a mechanism called the Pseudomonas Quinolone System (PQS). Two proteins in the PQS, PqsA and PqsD, were targeted for in silico ligand docking. The protein targets and potential ligand candidates were characterized and assessed. Ligands with high binding affinity (ΔG ≤ -9 kcal/mol) were identified via molecular docking of 6,699 pre-screened molecules from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The top 20 ligands for each target protein were selected based on binding affinity, adherence to Lipinski’s Rule of Five, rotatable bond count, and number of hydrophobic and hydrophilic bonds. To further increase the binding affinities, ten new ligands were designed for each protein by using different combinations of the screened ligands, and modifying them. Three novel ligands with high binding energies (ΔG ≤ -9.1 kcal/mol) for each target protein were selected. MOL001462, MOL008632, and MOL008648 are the top binding ligands for PqsA from the TCMSP database. MOL000738x003598, MOL006669x011160, and MOL003841x008243 are the top redesigned molecules for this protein. MOL004384, MOL013063, MOL012761 are the top binding TCMSP molecules for PqsD. MOL4384x10194, MOL12761x3207x10194, and MOL12761x10194 are the top redesigned molecules for this protein.