Computational Method for Structure-Based Analysis of SAR Transfer.,Journal of Medicinal Chemistry

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Computational Method for Structure-Based Analysis of SAR Transfer.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-15 , DOI: 10.1021/acs.jmedchem.9b01931
Davide Bonanni _{1,

2} , Marco L Lolli ₁ , Jürgen Bajorath ₂

Affiliation

The identification of different compound series with corresponding structure-activity relationship (SAR) progression for a given target is referred to as SAR transfer, which is of interest in lead optimization. If difficulties are encountered during multiproperty optimization, the SAR transfer concept can be applied attempting to replace a lead compound with another candidate. For a systematic assessment of SAR transfer, computational approaches are required. So far, SAR transfer has been investigated at the level of compounds and analogue series. Herein, we introduce a new computational method for structure-guided exploration of SAR transfer. The approach relies on a three-dimensional molecular fragmentation and recombination scheme and the identification of analogues of crystallographic ligands. On the basis of spatially aligned X-ray ligands, alternative substituents and compound cores are identified, enabling the detection of multiple SAR transfer events. Application of the methodology across different targets identified SAR transfer events with high frequency.

中文翻译：

基于结构的SAR传输分析的计算方法。

对于给定的目标，具有相应的构效关系（SAR）进行的不同化合物序列的鉴定称为SAR转移，这在潜在客户优化中很有意义。如果在多属性优化过程中遇到困难，则可以应用SAR转移概念，尝试用另一种替代物替换先导化合物。为了系统评估SAR传输，需要使用计算方法。到目前为止，已经在化合物和类似物系列的水平上研究了SAR转移。在此，我们介绍了一种用于结构指导的SAR传输探索的新计算方法。该方法依赖于三维分子破碎和重组方案以及晶体配体类似物的鉴定。根据空间排列的X射线配体，确定了替代的取代基和化合物核，从而能够检测多个SAR转移事件。该方法在不同目标上的应用确定了高频的SAR转移事件。

更新日期：2020-01-15

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