Towards uncoding hepatotoxicity of approved drugs through navigation of multiverse and consensus chemical spaces


Drug-induced liver injury (DILI) is the principal reason for failure in developing drug candidates. It is the most common reason to withdraw from the market after a drug has been approved for clinical use. Therefore, a current challenge is enhancing the accuracy of DILI events' predictive models. In this context, data from animal models, liver function tests, and chemical properties could complement each other to understand DILI events better and prevent them. Since the chemical space concept improves decision-making drug design related to the prediction of structure-property relationships, side effects, and polypharmacology drug activity (uniquely mentioning the most recent advances), it is an attractive approach to combining different phenomena influencing DILI events (e.g., individual “chemical spaces”) and exploring all events simultaneously in an integrated analysis of the DILI-relevant chemical space. However, currently, no systematic methods allow the fusion of a collection of different chemical spaces to collect different types of data on a unique chemical space representation, namely "consensus chemical space." This study is the first report that uses the data fusion concept to combine different chemical spaces to facilitate the analysis and prediction of DILIrelated events. The present work remarks the importance of analyzing together in vitro and chemical data (e.g., topology, bond order, atom types, presence of rings, ring sizes, and aromaticity of compounds encoded on RDKIT fingerprints). These properties could be aimed at improving the understanding of DILI events.


Supplementary weblinks

Supplementary Material
Dataset with 471 compounds associated with DILI reports (DB_ConsensusChemSpace_DILI.csv); The KNIME workflow (Multitiverse_DataFusion.knwf); Criteria to delimit each region (MetricOfDataFusion.xlsx); Definition of nine regions in the t-SNE plots (Fig_S1.png); Interactive visualizations of the chemical spaces (DB_ConsensusChemSpace_DILI.dwar).