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Exploration of multiple Sortase A protein conformations in virtual screening

Artikel i vetenskaplig tidskrift
Författare C. X. Gao
Ivana Uzelac
Johan Gottfries
Leif A Eriksson
Publicerad i Scientific Reports
Volym 6
Nummer/häfte 20413
ISSN 2045-2322
Publiceringsår 2016
Publicerad vid Institutionen för kemi och molekylärbiologi
Språk en
Länkar dx.doi.org/10.1038/srep20413
Ämnesord 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
Ämneskategorier Analytisk kemi

Sammanfattning

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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