SAR by Space: Enriching Hit Sets from the Chemical Space
SAR by Space: Enriching Hit Sets from the Chemical Space
复制标题
DOI：
10.3390/molecules24173096
复制
发表时间：
2019-09-01
期刊：
影响因子：
4.6
通讯作者：
Moroz, Yurii S.
中科院分区：
文献类型：
--
作者：
Klingler, Franca-Maria;Gastreich, Marcus;Moroz, Yurii S.
我们引入了空间构效关系的概念，通过合成来自巨大化学空间的邻近化合物来极大地加速结构-活性关系(SAR)的阐明。太空导航是在负担得起的标准计算机硬件上使用基于树的分子描述符和动态规划在几分钟内完成的。最大限度地提高计算机结果的综合可及性，是通过应用仔细选择的积木和适当选择的反应来实现的；十年的内部质量控制表明，这是这一过程中的关键部分。真正的太空是商业上可获得的化合物中最大的化学空间，截至目前，有110亿个分子。它被用来开采抗溴域4(BRD4)的活性。在合成之前，化合物使用计分函数对接到结合位置，该函数结合了固有的去溶项，从而避免了耗时的模拟。在不到六周的时间里，已经确定和验证了五个微摩尔命中，包括IC50值的测量。我们的结论是，这个过程大大节省了时间，在命中生成和先导优化阶段加速了配体和基于结构的方法。
We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages.