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Identification of potential inhibitors for LLM of Staphylococcus aureus: structure-based pharmacophore modeling,
1Department of Mathematics and Statistics, Swami Vivekanand Subharti University, Meerut, India.
Abstract:
Staphylococcus aureus causes various life-threatening diseases in humans and developed resistance to several antibiotics. Lipophilic membrane (LLM) protein regulates bacterial lysis rate and methicillin resistance level in S. aureus. To identify potential lead molecules, we performed a structure-based pharmacophore modeling by consideration of pharmacophore properties from LLM-tunicamycin complex. Further, virtual screening of ZINC database against the LLM was conducted and compounds were assessed for Lipinski and ADMET properties. Based on pharmacokinetic, and molecular docking, five potential inhibitors (ZINC000072380005, ZINC000257219974, ZINC000176045471, ZINC000035296288, and ZINC000008789934) were identified. Molecular dynamics simulation (MDS) of these five molecules was performed to evaluate the dynamics and stability of protein after binding of the ligands. Several MDS analysis like RMSD, RMSF, Rg, SASA, and PCA confirm that identified compounds exhibit higher binding affinity as compared to tunicamycin for LLM. The binding free energy analysis reveals that five compounds exhibit higher binding energy in the range of -218.76 to -159.52 kJ/mol, which is higher as compared to tunicamycin (-116.13 kJ/mol). Individual residue decomposition analysis concludes that Asn148, Asp151, Asp208, His271, and His272 of LLM play a significant role in the formation of lower energy LLM-inhibitor(s) complexes. These predicted molecules displayed pharmacological and structural properties and may be further used to develop novel antimicrobial compounds against S. aureus.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified five novel compounds targeting the Lipophilic Membrane protein (LLM) in Staphylococcus aureus. These compounds show strong binding affinity, offering potential for new antibiotic development against resistant bacteria.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Staphylococcus aureus infections pose significant health risks due to increasing antibiotic resistance.
- The Lipophilic Membrane protein (LLM) is crucial for regulating bacterial lysis and methicillin resistance in S. aureus.
Purpose of the Study:
- To identify novel small molecules that inhibit the LLM protein of S. aureus.
- To evaluate the binding affinity and stability of potential LLM inhibitors using computational methods.
Main Methods:
- Structure-based pharmacophore modeling using the LLM-tunicamycin complex.
- Virtual screening of the ZINC database against the LLM.
- Assessment of Lipinski's rule of five and ADMET properties.
- Molecular docking, molecular dynamics simulations (MDS), and binding free energy analysis.
Main Results:
- Five potential LLM inhibitors (ZINC000072380005, ZINC000257219974, ZINC000176045471, ZINC000035296288, ZINC000008789934) were identified.
- MDS confirmed higher binding affinity and stability of the identified compounds compared to tunicamycin.
- Binding free energy analysis indicated strong interactions, with values ranging from -159.52 to -218.76 kJ/mol.
Conclusions:
- The identified compounds exhibit promising pharmacological and structural properties for targeting S. aureus.
- These molecules represent potential lead candidates for developing novel antimicrobial agents against antibiotic-resistant S. aureus strains.
