Discovery of novel peptide deformylase inhibitors: Ensemble complex-based pharmacophore modeling, docking and binding affinity studies

Pseudomonas aeruginosa infections are quickly increasing in association with a variety of illnesses, necessitating the development of novel medications. This study employed an in silico technique to find PDF inhibitors against P. aeruginosa Peptide deformylase (PaPDF). PaPDF's structure is comparable to that of other PDFs; however, binding site studies found that PaPDF has a smaller pocket than Staphylococcus aureus, covering the S1 and S2 sub pockets, and maintains a conserved hydrophobic nature. The Zn metal binding site of modified PaPDFs was examined using molecular dynamics, and the results revealed that Cys92Ala differed from His134Ala and His138Ala, respectively. Complex-based pharmacophore investigation revealed three significant pharmacophoric characteristics within the pocket: two hydrophobic and one H-bond acceptor. This allows us to perform virtual screening using the ChemBride database to uncover a variety of potential hits with specific inhibitory characteristics. Several restrictions, including docking and molecular mechanics/general born-volume integral implicit solvent (MM/GBVI), were applied, and the top-ranked ligands were tested for inhibitory characteristics against key residues in the active site. Furthermore, the bioavailability and toxicity prediction identified seven potential leads and suggested future research into the design and synthesis of a unique class of PaPDF inhibitors.