Ensemble Docking as a Tool for the Rational Design of Peptidomimetic Staphylococcus aureus Sortase A Inhibitors

Area of Science:

• Microbiology
• Drug Discovery
• Computational Chemistry

Background:

• Sortase A (SrtA) from *Staphylococcus aureus* is a key target for developing antivirulence antibacterial agents.
• SrtA inhibitors offer a promising strategy to reduce antimicrobial resistance due to less evolutionary pressure.
• Developing effective SrtA inhibitors has been challenging due to difficulties in structure-based drug design.

Purpose of the Study:

• To develop a robust computational protocol for designing novel SrtA inhibitors.
• To improve the rational design of peptidomimetic inhibitors by accurately representing SrtA conformations.
• To prioritize new peptidomimetic molecules for synthesis and testing against SrtA.

Main Methods:

• Utilized molecular dynamics simulations to extract relevant SrtA conformations.
• Employed an ensemble docking approach to model the LPRDA-SrtA complex.
• Applied the developed protocol to screen and prioritize novel peptidomimetic inhibitors.

Main Results:

• The ensemble docking protocol effectively represented diverse SrtA conformations.
• The method showed good correlation with existing experimental data.
• Identified and prioritized new peptidomimetic structures for further investigation.

Conclusions:

• The proposed ensemble docking approach enhances the rational design of SrtA inhibitors.
• This method addresses limitations in traditional structure-based drug design for SrtA.
• The findings provide a foundation for developing new antivirulence therapies against *Staphylococcus aureus*.