Deep Learning-Assisted Repurposing of Plant Compounds for Treating Vascular Calcification: An In Silico Study with Experimental Validation

Abstract

Background. Vascular calcification (VC) constitutes subclinical vascular burden and increases cardiovascular mortality. Effective therapeutics for VC remains to be procured. We aimed to use a deep learning-based strategy to screen and uncover plant compounds that potentially can be repurposed for managing VC. Methods. We integrated drugome, interactome, and diseasome information from Comparative Toxicogenomic Database (CTD), DrugBank, PubChem, Gene Ontology (GO), and BioGrid to analyze drug-disease associations. A deep representation learning was done using a high-level description of the local network architecture and features of the entities, followed by learning the global embeddings of nodes derived from a heterogeneous network using the graph neural network architecture and a random forest classifier established for prediction. Predicted results were tested in an in vitro VC model for validity based on the probability scores. Results. We collected 6,790 compounds with available Simplified Molecular-Input Line-Entry System (SMILES) data, 11,958 GO terms, 7,238 diseases, and 25,482 proteins, followed by local embedding vectors using an end-to-end transformer network and a node2vec algorithm and global embedding vectors learned from heterogeneous network via the graph neural network. Our algorithm conferred a good distinction between potential compounds, presenting as higher prediction scores for the compound categories with a higher potential but lower scores for other categories. Probability score-dependent selection revealed that antioxidants such as sulforaphane and daidzein were potentially effective compounds against VC, while catechin had low probability. All three compounds were validated in vitro. Conclusions. Our findings exemplify the utility of deep learning in identifying promising VC-treating plant compounds. Our model can be a quick and comprehensive computational screening tool to assist in the early drug discovery process.