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

Lingling Shen; Jian Fang; Lulu Liu; Fei Yang; Jeremy L Jenkins; Peter S Kutchukian; He Wang

doi:10.1186/s13321-024-00829-w

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

J Cheminform. 2024 Mar 21;16(1):33. doi: 10.1186/s13321-024-00829-w.

Authors

Lingling Shen^#¹, Jian Fang^#², Lulu Liu², Fei Yang², Jeremy L Jenkins², Peter S Kutchukian², He Wang³

Affiliations

¹ Novartis Biomedical Research, Cambridge, MA, 02139, USA. lingling.shen@novartis.com.
² Novartis Biomedical Research, Cambridge, MA, 02139, USA.
³ Novartis Biomedical Research, Cambridge, MA, 02139, USA. he.wang@novartis.com.

^# Contributed equally.

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.

Keywords: 3D generative chemistry; Drug discovery; Hit finding; Pocket Crafter; WDR5.