Controlling astrocyte-mediated synaptic pruning signals for schizophrenia drug repurposing with Deep Graph Networks

Abstract

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia. Author summaryPhagocytosis is a fundamental biological process to protect biological organisms from exogenous infectious particles as well as to preserve equilibrium and efficiency of the host by removing its unwanted cells. A dysregulation of the phagocytic activity can lead to severe consequences for the host. In this study, we focus on a recent theory that relates an excessive phagocytic activity in brain cells, and a consequent abnormal reduction in brain volume, to the development of schizophrenia. Our working hypothesis is that pharmaceutical compounds that can reduce excessive of phagocytic activity might prove effective as a schizophrenia treatment. Rather than attempting to develop ex-novo such a chemical compound, we rely on a more cost-effective and efficient approach that seeks candidate therapies in a set of approved chemical compounds. To achieve this, we train a machine learning model capable of predicting, with good accuracy, the ability of a molecular compound to increase or decrease phagocytosis in the target brain cells. Our approach leverages learning models capable of directly processing the molecular graph of the compound, leading to the identification of 64 candidate drugs of potential clinical utility.