An Aggregation Advisor for Ligand Discovery.
An Aggregation Advisor for Ligand Discovery.
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DOI：
10.1021/acs.jmedchem.5b01105
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发表时间：
2015-09-10
影响因子：
7.3
通讯作者：
Shoichet BK
中科院分区：
文献类型：
--
作者：
Irwin JJ;Duan D;Torosyan H;Doak AK;Ziebart KT;Sterling T;Tumanian G;Shoichet BK
有机分子的胶体聚集是人为抑制蛋白质的主要机制，并且针对其的控制被广泛部署。尽管对这一现象有了越来越详细的了解，但可靠地预测聚集的方法仍然难以捉摸。相应地，通过聚集起作用的活性分子继续在早期发现活动中被发现，并且在文献中仍然很常见。在过去的十年中，已经确定了超过1.2万个聚集的有机分子，这可能使基于先例的方法能够将已知的聚合物与可能会聚集并导致人工制品的新分子相匹配。我们研究了一种方法，使用亲脂性，亲和力和相似性已知的聚集建议的可能性，候选化合物是一个聚集。在前瞻性的实验测试中，五个新的分子与Tanimoto系数（Tc）在0.95和0.99之间的已知的聚集剂聚集在相关浓度。Tc在0.94和0.90之间的19个中的10个和Tc在0.89和0.85之间的7个中的3个也聚集。另外三种预测的化合物聚集在更高的浓度。该方法发现，药物化学文献中在0.1至10 µM范围内作用的61827或5.1%的配体与具有这些物理性质的已知聚集剂至少85%相似，并且可能在相关浓度下聚集。有趣的是，只有0.73%的类似药物的市售化合物类似于已知的聚集剂，这表明胶体聚集剂在文献中富集。作为文献的百分比，自1995年以来，聚集体样化合物增加了9倍，部分反映了针对分子靶点的高通量和虚拟筛选的出现。从这项研究中出现的是一个聚合顾问数据库和工具（advisor.bkslab.org），免费提供给社区，这可能有助于区分富有成效的和人为的筛选命中通过这种机制。
Colloidal aggregation of organic molecules is the dominant mechanism for artifactual inhibition of proteins, and controls against it are widely deployed. Notwithstanding an increasingly detailed understanding of this phenomenon, a method to reliably predict aggregation has remained elusive. Correspondingly, active molecules that act via aggregation continue to be found in early discovery campaigns and remain common in the literature. Over the past decade, over 12 thousand aggregating organic molecules have been identified, potentially enabling a precedent-based approach to match known aggregators with new molecules that may be expected to aggregate and lead to artifacts. We investigate an approach that uses lipophilicity, affinity, and similarity to known aggregators to advise on the likelihood that a candidate compound is an aggregator. In prospective experimental testing, five of seven new molecules with Tanimoto coefficients (Tc’s) between 0.95 and 0.99 to known aggregators aggregated at relevant concentrations. Ten of 19 with Tc’s between 0.94 and 0.90 and three of seven with Tc’s between 0.89 and 0.85 also aggregated. Another three of the predicted compounds aggregated at higher concentrations. This method finds that 61 827 or 5.1% of the ligands acting in the 0.1 to 10 µM range in the medicinal chemistry literature are at least 85% similar to a known aggregator with these physical properties and may aggregate at relevant concentrations. Intriguingly, only 0.73% of all drug-like commercially available compounds resemble the known aggregators, suggesting that colloidal aggregators are enriched in the literature. As a percentage of the literature, aggregator-like compounds have increased 9-fold since 1995, partly reflecting the advent of high-throughput and virtual screens against molecular targets. Emerging from this study is an aggregator advisor database and tool (http://advisor.bkslab.org), free to the community, that may help distinguish between fruitful and artifactual screening hits acting by this mechanism.