Transporter proteins knowledge graph construction and its application in drug development

Abstract

Transporters are the main determinant for pharmacokinetics characteristics of drugs, such as absorption, distribution, and excretion of drugs in humans. However, it is difficult to perform drug transporter validation and structure analysis of membrane transporter proteins by experimental methods. Many studies have demonstrated that knowledge graphs (KG) could effectively excavate potential association information between different entities. To improve the effectiveness of drug discovery, a transporter-related KG was constructed in this study. Meanwhile, a predictive frame (AutoInt_KG) and a generative frame (MolGPT_KG) were established based on the heterogeneity information obtained from the transporter-related KG by the RESCAL model. Natural product Luteolin with known transporters was selected to verify the reliability of the AutoInt_KG frame, its ROC-AUC (1:1), ROC-AUC (1:10), PR-AUC (1:1), PR-AUC (1:10) are 0.91, 0.94, 0.91 and 0.78, respectively. Subsequently, the MolGPT_KG frame was constructed to implement efficient drug design based on transporter structure. The evaluation results showed that the MolGPT_KG could generate novel and valid molecules and that these molecules were further confirmed by molecular docking analysis. The docking results showed that they could bind to important amino acids at the active site of the target transporter. Our findings will provide rich information resources and guidance for the further development of the transporter-related drugs.