Molecular Graph-Based Deep Learning Algorithm Facilitates an Imaging-Based Strategy for Rapid Discovery of Small Molecules Modulating Biomolecular Condensates.
Journal:
Journal of medicinal chemistry
Published Date:
Nov 23, 2023
Abstract
Biomolecular condensates are proposed to cause diseases, such as cancer and neurodegeneration, by concentrating proteins at abnormal subcellular loci. Imaging-based compound screens have been used to identify small molecules that reverse or promote biomolecular condensates. However, limitations of conventional imaging-based methods restrict the screening scale. Here, we used a graph convolutional network (GCN)-based computational approach and identified small molecule candidates that reduce the nuclear liquid-liquid phase separation of TAR DNA-binding protein 43 (TDP-43), an essential protein that undergoes phase transition in neurodegenerative diseases. We demonstrated that the GCN-based deep learning algorithm is suitable for spatial information extraction from the molecular graph. Thus, this is a promising method to identify small molecule candidates with novel scaffolds. Furthermore, we validated that these candidates do not affect the normal splicing function of TDP-43. Taken together, a combination of an imaging-based screen and a GCN-based deep learning method dramatically improves the speed and accuracy of the compound screen for biomolecular condensates.