PDF(Pubmed)
Abstract：
We present a user-friendly molecular generative pipeline called Pocket Crafter, specifically designed to facilitate hit finding activity in the drug discovery process. This workflow utilized a three-dimensional (3D) generative modeling method Pocket2Mol, for the de novo design of molecules in spatial perspective for the targeted protein structures, followed by filters for chemical-physical properties and drug-likeness, structure-activity relationship analysis, and clustering to generate top virtual hit scaffolds. In our WDR5 case study, we acquired a focused set of 2029 compounds after a targeted searching within Novartis archived library based on the virtual scaffolds. Subsequently, we experimentally profiled these compounds, resulting in a novel chemical scaffold series that demonstrated activity in biochemical and biophysical assays. Pocket Crafter successfully prototyped an effective end-to-end 3D generative chemistry-based workflow for the exploration of new chemical scaffolds, which represents a promising approach in early drug discovery for hit identification.
摘要：
我们提出了一种用户友好的分子生成管道，称为PocketCrafter，专门设计用于促进药物发现过程中的命中发现活动。此工作流程利用了三维（3D）生成建模方法Pocket2Mol，对于从空间角度对分子进行从头设计，用于靶向蛋白质结构，然后是化学物理特性和药物相似性的过滤器，结构-活性关系分析，和群集以生成顶级虚拟命中脚手架。在我们的WDR5案例研究中，在基于虚拟支架的诺华存档库中进行有针对性的搜索后,我们获得了一组集中的2029种化合物.随后，我们通过实验分析了这些化合物，产生了一种新型的化学支架系列，该系列在生化和生物物理测定中表现出活性。PocketCrafter成功地制作了一个有效的端到端3D生成化学工作流程的原型，用于探索新的化学支架，这代表了早期药物发现中用于命中识别的有希望的方法。
