DrugRepPT: a deep pretraining and fine-tuning framework for drug repositioning based on drug’s expression perturbation and treatment effectiveness

Abstract

Motivation: Drug repositioning (DR), identifying novel indications for approved drugs, is a cost-effective strategy in drug discovery. Despite numerous proposed DR models, integrating network-based features, differential gene expression, and chemical structures for high-performance DR remains challenging. Results: We propose a comprehensive deep pretraining and fine-tuning framework for DR, termed DrugRepPT. Initially, we design a graph pretraining module employing model-augmented contrastive learning on a vast drug–disease heterogeneous graph to capture nuanced interactions and expression perturbations after intervention. Subsequently, we introduce a fine-tuning module leveraging a graph residual-like convolution network to elucidate intricate interactions between diseases and drugs. Moreover, a Bayesian multiloss approach is introduced to balance the existence and effectiveness of drug treatment effectively. Extensive experiments showcase the efficacy of our framework, with DrugRepPT exhibiting remarkable performance improvements compared to SOTA (state of the arts) baseline methods (improvement 106.13% on Hit@1 and 54.45% on mean reciprocal rank). The reliability of predicted results is further validated through two case studies, i.e. gastritis and fatty liver, via literature validation, network medicine analysis, and docking screening. Availability and implementation: The code and results are available at https://github.com/2020MEAI/DrugRepPT.