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Updated: Mar 26, 2026
Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source
Published on: May 29, 2021
Exploration of multiple Sortase A protein conformations in virtual screening
Chunxia Gao1, Ivana Uzelac1, Johan Gottfries1
1Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
Abstract:
Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.
Insights
New research explores inhibiting Methicillin-resistant Staphylococcus aureus (MRSA) by targeting the S. aureus Sortase A (SrtA) enzyme. Understanding protein flexibility and binding modes is key to developing effective antivirulence agents against resistant bacterial strains.
Area of Science:
- Microbiology
- Biochemistry
- Computational Chemistry
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) presents a significant global health challenge, necessitating novel therapeutic strategies.
- The bacterial enzyme S. aureus Sortase A (SrtA) is crucial for bacterial adherence, making it a promising target for antivirulence therapies, including against resistant strains.
Purpose of the Study:
- To investigate the impact of protein structural flexibility on virtual screening performance for SrtA inhibitors.
- To explore the binding modes of small molecules to SrtA using diverse receptor structures.
Main Methods:
- Employed molecular dynamics simulations (regular and steered) to generate 100 SrtA structures from four distinct crystal/NMR templates.
- Performed virtual screening using 10 known binders and 500 decoys against the generated SrtA structures.
Main Results:
- Identified a correlation between SrtA protein structural flexibility and virtual screening success.
- Confirmed the immobilization of the β6/β7 loop upon substrate binding.
- Observed that NMR-derived SrtA structures showed slightly better screening performance than X-ray crystal structures.
Conclusions:
- Protein structural flexibility significantly influences the efficacy of virtual screening for SrtA inhibitors.
- Binding modes of inhibitors are highly dynamic and may not always involve the catalytic site, suggesting alternative binding pockets.
- Further research is needed to fully elucidate the complex binding interactions of SrtA inhibitors.
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