Shen, Lingling, Fang, Jian, Jenkins, Jeremy, Kutchukian, Peter and Wang, He (2024) Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery. Journal of cheminformatics, 16 (1). p. 33. ISSN 1758-2946

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.

Item Type:	Article
Date Deposited:	25 Jun 2024 00:46
Last Modified:	25 Jun 2024 00:46
URI:	https://oak.novartis.com/id/eprint/50807