Hosseini-Gerami, L. | bioRxiv Science

bioRxiv2023

Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA DICTrank

Drug-induced cardiotoxicity (DICT) is a major concern in drug development, accounting for 10-14% of postmarket withdrawals. In this study, we explored the capabilities of various chemical and biological data to predict cardiotoxicity, using the recently released Drug-Induced Cardiotoxicity Rank (DICTrank) dataset from the United States FDA. We analyzed a diverse set of data sources, including physicochemical properties, annotated mechanisms of action (MOA), Cell Painting, Gene Expression, and more, to identify indications of cardiotoxicity. We found that such data, including protein targets, especially those related to ion channels (such as hERG), physicochemical properties (such as electrotopological state) as well as peak concentration in plasma offer strong predictive ability as well as valuable insights into DICT. We also found compounds annotated with particular mechanisms of action, such as cyclooxygenase inhibition, could distinguish between most-concern and no-concern DICT compounds. Cell Painting features related to ER stress discern the most-concern cardiotoxic compounds from non-toxic compounds. While models based on physicochemical properties currently provide substantial predictive accuracy (AUCPR = 0.93), this study also underscores the potential benefits of incorporating more comprehensive biological data in future DICT predictive models. With the availability of - omics data in the future, using biological data promises enhanced predictability and delivers deeper mechanistic insights, paving the way for safer therapeutic drug development. All models and data used in this study are publicly released at https://broad.io/DICTrank_Predictor O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/562398v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@755906org.highwire.dtl.DTLVardef@27c43borg.highwire.dtl.DTLVardef@c430dborg.highwire.dtl.DTLVardef@63b2ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

MAVEN: An R/Shiny app for compound mechanism of action analysis and visualisation using transcriptomics and compound structure data

BackgroundUnderstanding the mechanism of action (MoA) of a compound is an often challenging but equally crucial aspect of drug discovery that can help improve both its efficacy and safety. Computational methods to aid MoA elucidation usually either aim to predict direct drug targets, or attempt to understand modulated downstream pathways or signalling proteins. Such methods usually require extensive coding experience and results are often optimised for further computational processing, making them difficult for wet-lab scientists to perform, interpret and draw hypotheses from. ResultsTo address this issue, we in this work present MAVEN (Mechanism of Action Visualisation and Enrichment), an R/Shiny app which allows for GUI-based prediction of drug targets based on chemical structure, combined with causal reasoning based on causal protein-protein interactions and transcriptomic perturbation signatures. The app computes a systems-level view of the mechanism of action of the input compound. This is visualised as a sub-network linking predicted or known targets to modulated transcription factors via inferred signalling proteins. The tool includes a selection of MsigDB gene set collections to perform pathway enrichment on the resulting network, and also allows for custom gene sets to be uploaded by the researcher. MAVEN is hence a user-friendly, flexible tool for researchers without extensive bioinformatics or cheminformatics knowledge to generate interpretable hypotheses of compound Mechanism of Action. ConclusionsMAVEN is available as a fully open-source tool at https://github.com/laylagerami/MAVEN with options to install in a Docker or Singularity container. Full documentation, including a tutorial on example data, is available at https://laylagerami.github.io/MAVEN.

systems biology↗