Identification of novel non-hydroxamate anthrax toxin lethal factor inhibitors by topomeric searching, docking and scoring, and in vitro screening.
Identification of novel non-hydroxamate anthrax toxin lethal factor inhibitors by topomeric searching, docking and scoring, and in vitro screening.
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DOI：
10.1021/ci900186w
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发表时间：
2009-12
影响因子：
5.6
通讯作者：
Amin EA
中科院分区：
文献类型：
--
作者：
Chiu TL;Solberg J;Patil S;Geders TW;Zhang X;Rangarajan S;Francis R;Finzel BC;Walters MA;Hook DJ;Amin EA
炭疽是一种由炭疽杆菌引起的传染病，炭疽杆菌是一种革兰氏阳性、杆状、厌氧细菌。致死因子（LF）酶由炭疽芽孢杆菌分泌，作为三联外毒素的一部分，主要负责炭疽相关的细胞毒性。由于在抗生素从体内根除炭疽芽孢杆菌后，LF 仍可以在系统中保留很长时间，因此首选的治疗方式是抗生素与有效的 LF 抑制剂一起使用。尽管 LF 作为合理药物设计的有吸引力的靶点而受到广泛关注，但相对较少的已发表抑制剂在基于细胞的测定中显示出活性，并且迄今为止，还没有 LF 抑制剂可用作治疗或预防剂。在这里，我们提出了一种新颖的计算机高通量虚拟筛选方案，该方案成功鉴定出 5 种非异羟肟酸小分子作为新的初步 LF 抑制剂支架，对该靶标具有低微摩尔抑制，实验命中率为 12.8%。该方案筛选了大约 3500 万种非冗余化合物的潜在抗 LF 活性，包括拓扑搜索、对接和评分以及类药物过滤。在这 5 种命中化合物中，没有一种化合物之前被鉴定为 LF 抑制剂，其中三种化合物的实验 IC50 值小于 100 µM。这三个初步命中可能作为先导化合物优化的支架，以及用于机制研究的探针化合物的模板。值得注意的是，我们的对接模拟预测，这些新的命中可能与 LF 底物结合区域三个亚位点（S1'、S1-S2 和 S2'）中的至少两个附近的残基发生关键的配体-受体相互作用。这些化合物的进一步实验表征正在进行中。我们发现，只要保留与至少两个 LF 亚位点的关键疏水相互作用，具有单齿锌螯合的非异羟肟酸锌结合基团的化合物就可以实现微摩尔水平的 LF 抑制。
Anthrax is an infectious disease caused by Bacillus anthracis, a Gram-positive, rod-shaped, anaerobic bacterium. The lethal factor (LF) enzyme is secreted by B. anthracis as part of a tripartite exotoxin and is chiefly responsible for anthrax-related cytotoxicity. As LF can remain in the system long after antibiotics have eradicated B. anthracis from the body, the preferred therapeutic modality would be the administration of antibiotics together with an effective LF inhibitor. Although LF has garnered a great deal of attention as an attractive target for rational drug design, relatively few published inhibitors have demonstrated activity in cell-based assays and, to date, no LF inhibitor is available as a therapeutic or preventive agent. Here we present a novel in silico high-throughput virtual screening protocol that successfully identified 5 non-hydroxamic acid small molecules as new, preliminary LF inhibitor scaffolds with low micromolar inhibition against that target, resulting in a 12.8% experimental hit rate. This protocol screened approximately thirty-five million non-redundant compounds for potential activity against LF and comprised topomeric searching, docking and scoring, and drug-like filtering. Among these 5 hit compounds, none of which has previously been identified as a LF inhibitor, three exhibited experimental IC50 values less than 100 µM. These three preliminary hits may potentially serve as scaffolds for lead optimization, as well as templates for probe compounds to be used in mechanistic studies. Notably, our docking simulations predicted that these novel hits are likely to engage in critical ligand-receptor interactions with nearby residues in at least two of the three (S1’, S1–S2 and S2’) subsites in the LF substrate binding area. Further experimental characterization of these compounds is in process. We found that micromolar-level LF inhibition can be attained by compounds with non-hydroxamate zinc-binding groups that exhibit monodentate zinc chelation, as long as key hydrophobic interactions with at least two LF subsites are retained.
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