MOASL: Predicting drug mechanism of actions through similarity learning with transcriptomic signature.

Understanding the mechanisms of actions (MOAs) of compounds is crucial in drug discovery. A common step in drug MOAs annotation is to query the dysregulated gene signatures induced by drugs in a reference library of pre-defined signatures. However, traditional similarity-based computational strategies face challenges when dealing with high-dimensional and noisy transcriptional signature data. To address this issue, we introduce MOASL (MOAs prediction via Similarity Learning), a novel approach that contrastive to learn similarity embeddings among signatures with shared MOAs automatically. We evaluated the accuracy of signature matching on various transcriptional activity score (TAS) datasets and individual cell lines by using MOASL. The results show MOASL achieved higher performance over several statistical and machine learning methods. Furthermore, we provided the rationale of our model by visualizing the signature annotation procedure. Using MOASL, the MOAs label of query signature could be conveniently defined by calculating the similarity between the query embedding and the reference embeddings. Finally, we applied MOASL to repurpose thousands of compounds as glucocorticoid receptor (GR) agonists, accurately identifying 8 out of the top 10 compounds. MOASL is conveniently accessible on GitHub at https://github.com/jianglikun/MOASL, empowering researchers and practitioners in the field of drug discovery to predict the MOAs of drug.