BioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, Germany.
Enamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, Ukraine.
Molecules. 2019 Aug 26;24(17):3096. doi: 10.3390/molecules24173096.
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 micromolecular 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.
我们引入了基于空间的 SAR（SAR-by-Space）方法，通过合成源自广阔化学空间的相邻化合物，可极大地加速构效关系（SAR）的阐明。使用基于树的分子描述符和动态编程，在价格合理的标准计算机硬件上，仅需几分钟即可完成空间导航。通过应用精心选择的构建模块并结合适当选择的反应，最大程度地提高计算机生成结果的合成可及性；十年来的内部质量控制表明，这是该过程的关键部分。REAL Space 是商业上可用化合物的最大化学空间，截至今天，已有 110 亿个分子。它被用于挖掘针对溴结构域蛋白 4（BRD4）的活性化合物。在合成之前，使用包含内在去溶剂化项的评分函数将化合物对接至结合位点，从而避免了耗时的模拟。在不到六周的时间内，已经鉴定并验证了五个微量分子，包括 IC50 值的测量。我们得出结论，该程序可大大节省时间，加速配体和基于结构的方法在发现和先导化合物优化阶段的应用。
