%0 Journal Article
%T Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery.
%A Shen L
%A Fang J
%A Liu L
%A Yang F
%A Jenkins JL
%A Kutchukian PS
%A Wang H
%J J Cheminform
%V 16
%N 1
%D 2024 Mar 21
%M 38515171
%F 8.489
%R 10.1186/s13321-024-00829-w
%X 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.