{Reference Type}: Journal Article
{Title}: Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery.
{Author}: Shen L;Fang J;Liu L;Yang F;Jenkins JL;Kutchukian PS;Wang H;
{Journal}: J Cheminform
{Volume}: 16
{Issue}: 1
{Year}: 2024 Mar 21
{Factor}: 8.489
{DOI}: 10.1186/s13321-024-00829-w
{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.