Computational and experimental prediction of human C-type lectin receptor druggability.
Computational and experimental prediction of human C-type lectin receptor druggability.
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DOI：
10.3389/fimmu.2014.00323
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发表时间：
2014
影响因子：
7.3
通讯作者：
Rademacher C
中科院分区：
文献类型：
--
作者：
Aretz J;Wamhoff EC;Hanske J;Heymann D;Rademacher C
哺乳动物c型凝集素受体（CTLRS）参与免疫细胞调控的许多方面，如病原体识别、凋亡小体清除和淋巴细胞归巢。尽管对调节碳水化合物的CTLR识别有很大的兴趣，但特定分子探针的数量有限。为此，我们使用dogsitescover预测了22个ctlr的可药物性。大多数结构的计算可药物性得分很低，这表明该家族要么具有挑战性，要么甚至是不可药物的。为了进一步探索这些发现，我们采用了基于氟的核磁共振筛选片段混合物对抗DC-SIGN，一种药理学感兴趣的受体。令我们惊讶的是，我们发现许多片段与碳水化合物识别位点相关（命中率= 13.5%）。基于表面等离子体共振的后续分析证实了其中18个片段（47%），并确定了平衡解离常数。受这些发现的鼓舞，我们将我们的实验性药物性预测扩展到Langerin和MCL，并发现中高命中率，分别为15.7%和10.0%。我们的研究结果强调了当前计算机方法在药物评估方面的局限性，特别是在碳水化合物结合蛋白方面。总之，我们的数据表明，可以开发用于更大范围ctlr的小分子配体。
Mammalian C-type lectin receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable. To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rate = 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
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影响因子：
64.5
作者：
Geijtenbeek, TBH;Torensma, R;Figdor, CG
通讯作者：
Figdor, CG
影响因子：
4.8
作者：
Feinberg, H;Park-Snyder, S;Weis, WI
通讯作者：
Weis, WI
影响因子：
15
作者：
Borrok, M. Jack;Kiessling, Laura L.
通讯作者：
Kiessling, Laura L.
影响因子：
3.5
作者：
Chen, I-Jen;Hubbard, Roderick E.
通讯作者：
Hubbard, Roderick E.
影响因子：
56.9
作者：
Feinberg, H;Mitchell, DA;Weis, WI
通讯作者：
Weis, WI