In Silico Lead Identification of Staphylococcus aureus LtaS Inhibitors: A High-Throughput Computational Pipeline...

Area of Science:

• Computational chemistry and drug discovery
• Microbiology and infectious diseases

Background:

• Emergence of multidrug-resistant Staphylococcus aureus necessitates new antimicrobial agents.
• Lipoteichoic acid synthase (LtaS) is a critical enzyme in Gram-positive bacteria and a potential drug target.

Purpose of the Study:

• To identify potent inhibitors of the LtaS enzyme using a computational approach.
• To evaluate the drug-likeness and pharmacokinetic properties of potential inhibitors.

Main Methods:

• Virtual screening of natural compounds from the COCONUT database against LtaS crystal structure (PDB ID: 2W5R).
• Multi-stage molecular docking (HTVS, SP, XP) followed by MM-GBSA calculations.
• Molecular dynamics (MD) simulations, Density Functional Theory (DFT) calculations, and ADMET profiling.

Main Results:

• Eight initial hits with diverse scaffolds were identified.
• Two compounds (Compound A and Compound B) demonstrated stable binding, favorable binding free energy, and acceptable ADMET profiles.
• DFT calculations indicated improved electronic stabilization and charge-transfer characteristics for the screened ligands.

Conclusions:

• The identified compounds (A and B) are promising orally active leads for developing novel anti-staphylococcal agents.
• Targeting LtaS presents a viable strategy against multidrug-resistant Staphylococcus aureus.
• Further experimental validation is recommended to confirm the efficacy of these lead compounds.