Gao Chunxia, Uzelac Ivana, Gottfries Johan, Eriksson Leif A
Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
Sci Rep. 2016 Feb 5;6:20413. doi: 10.1038/srep20413.
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.
耐甲氧西林金黄色葡萄球菌（MRSA）已成为一个重大的健康问题，这使得迫切需要新的治疗药物。由于金黄色葡萄球菌分选酶A（SrtA）酶有助于细菌粘附到宿主细胞上，因此小分子对其的抑制作用可作为潜在的抗毒力药物，对抗耐药菌株也有效。尽管已经报道了几次针对SrtA的虚拟对接研究，但尚未从中发现强抑制性的非共价结合剂。为了更好地理解小分子的结合模式以及筛选中使用的不同受体结构的影响，我们在此报告一项探索性研究，该研究使用10种已知结合剂和500种诱饵分子，对基于四种不同SrtA晶体/NMR结构通过常规或引导分子动力学模拟生成的100种SrtA结构进行研究。结果表明蛋白质结构灵活性与虚拟筛选性能之间存在相关性，并证实了在底物结合时β6/β7环的固定。所报道的NMR结构似乎比X射线晶体结构表现稍好，但结合模式波动极大，并且可能怀疑催化位点不一定是一些所报道的活性化合物的首选结合位点。
