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Exploration of multiple Sortase A protein conformations in virtual screening

Journal article
Authors C. X. Gao
Ivana Uzelac
Johan Gottfries
Leif A Eriksson
Published in Scientific Reports
Volume 6
Issue 20413
ISSN 2045-2322
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Language en
Keywords staphylococcus-aureus sortase, anchoring transpeptidase sortase, gram-positive bacteria, particle mesh ewald, molecular-dynamics, a, inhibitors, substrate complex, active-site, force-field, cell-wall, Science & Technology - Other Topics, war mjs, 1985, journal of the american chemical society, v107, p3902, iences, v367, p1123
Subject categories Analytical Chemistry


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 beta 6/beta 7 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.

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