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

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 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 .

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.