2,4-difluorophenyl(piperidin-4-yl) methanoneoxime derivatives as potent contenders to combat antibacterial resistance of MRSA: In-silico approach

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat as a primary contributor to bacterial infections in healthcare and community environments. Its resistance to various antibiotics poses challenges for treatment. Consequently, combating MRSA has become a central objective in infection control strategies worldwide. In this study, a series of 44 compounds was designed to identify potential inhibitors against MRSA proteins. Ligand-based pharmacophore modeling was employed using the PHASE module within Schrödinger’s Drug Design Suite, resulting in a five-featured model (DHHRR) comprising three hydrogen bond donors, a pair of hydrophobic entities, and two aromatic rings. The drug-likeness properties of the compounds were assessed using Lipinski's Rule of 5 and Veber's Rule, confirming their pharmacological attributes. Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) predictions evaluated the compounds' potential as viable drug candidates, and molecular docking studies against MRSA proteins like Staphylococcus aureus Gyrase protein (PDB ID: 2XCT), and Escherichia coli Penicillin Binding Protein 1b (PBP1b) (PDB ID: 5HL9) were performed. The top-ranked compound, 5k: (Z)-(2,4-difluorophenyl)(1-((4-hydroxyphenyl)sulfonyl)piperidin-4-yl)methanone oxime, exhibited strong interactions with both proteins, showcasing favorable binding energies of − 8.3 and − 8.0 kcal/mol for 2XCT and 5HL9. Molecular dynamics simulations were employed to study the stability of the protein–ligand complexes, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) analysis confirmed the strong binding free energy of 5k with the target proteins − 31.87 ± 2.67, and − 33.39 ± 7.84 kcal/mol for 2XCT and 5HL9. Lastly, Density Functional Theory (DFT) calculations provided insights into the electronic and molecular characteristics of 5k, revealing promising reactivity and chemical properties. Overall, compound 5k stands out as a promising candidate for MRSA inhibition based on Computational findings. However, further investigations are necessary to validate and confirm its potential as a novel MRSA inhibitor.