Cocaine addiction is a psychosocial disorder induced by the chronic use of cocaine and causes a large number of deaths around the world. Despite decades of effort, no drugs have been approved by the Food and Drug Administration (FDA) for the treatment of cocaine dependence. Cocaine dependence is neurological and involves many interacting proteins in the interactome. Among them, the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters are three major targets. Each of these targets has a large protein−protein interaction (PPI) network, which must be considered in the anticocaine addiction drug discovery. This work presents DAT, SERT, and NET interactome network-informed machine learning/deep learning (ML/DL) studies of cocaine addiction. We collected and analyzed 61 protein targets out of 460 proteins in the DAT, SERT, and NET PPI networks that have sufficiently large existing inhibitor datasets. Utilizing autoencoder (AE) and other ML/DL algorithms, including gradient boosting decision tree (GBDT) and multitask deep neural network (MT-DNN), we built predictive models for these targets with 115 407 inhibitors to predict drug repurposing potential and possible side effects. We further screened their absorption, distribution, metabolism, and excretion, and toxicity (ADMET) properties to search for leads having potential for developing treatments for cocaine addiction. Our approach offers a new systematic protocol for artificial intelligence (AI)-based anticocaine addiction lead discovery.

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Drug addiction is a global public health crisis, and the design of antiaddiction drugs remains a major challenge due to intricate mechanisms. Since experimental drug screening and optimization are too time-consuming and expensive, there is urgent need to develop innovative artificial intelligence (AI) methods for addressing the challenge. We tackle this challenge by topology-inferred drug addiction learning (TIDAL) built from integrating multiscale topological Laplacians, deep bidirectional transformer, and ensemble-assisted neural networks (EANNs). Multiscale topological Laplacians are a novel class of algebraic topology tools that embed molecular topological invariants and algebraic invariants into its harmonic spectra and nonharmonic spectra, respectively. These invariants complement sequence information extracted from a bidirectional transformer. We validate the proposed TIDAL framework on 22 drug addiction related, 4 hERG, and 12 DAT data sets, which suggests that the proposed TIDAL is a state-of-the-art framework for the modeling and analysis of drug addiction data. We carry out cross-target analysis of the current drug addiction candidates to alert their side effects and identify their repurposing potentials. Our analysis reveals drug-mediated linear and bilinear target correlations. Finally, TIDAL is applied to shed light on relative efficacy, repurposing potential, and potential side effects of 12 existing antiaddiction medications. Our results suggest that TIDAL provides a new computational strategy for pressingly needed antisubstance addiction drug development.