Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery

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. Hit identification is a time-consuming and costly step in drug discovery process. Here we developed a molecule generative pipeline called Pocket Crafter that can speed up this process greatly. This workflow utilized 3D generative modeling method Pocket2Mol for the de novo design of molecules in spatial perspective for the target and applies filters for chemical-physical properties and drug-likeness to generate top virtual hits with further structure-activity relationship analysis and clustering to output a focused set of hit compounds, which led to the success of hit finding as it showed in our demo case.