title: Exploration of multiple Sortase A protein conformations in virtual screening.
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.
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
authors: Chunxia
authors: C
authors: Gao
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
authors: Ivana
authors: I
authors: Uzelac
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
authors: Johan
authors: J
authors: Gottfries
authors: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
authors: Leif A
authors: LA
authors: Eriksson
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012372:ROC Curve; D013211:Staphylococcus aureus / Q000201:enzymology*; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases