文章基本信息

标题：Machine learning and structure-based modeling for the prediction of UDP-glucuronosyltransferase inhibition
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作者：Balint Dudas ; Youcef Bagdad ; Milan Picard 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：11
页码：1-16
DOI：10.1016/j.isci.2022.105290
语种：English
出版社：Elsevier
摘要：SummaryUDP-glucuronosyltransferases (UGTs) are responsible for 35% of the phase II drug metabolism. In this study, we focused on UGT1A1, which is a key UGT isoform. Strong inhibition of UGT1A1 may trigger adverse drug/herb-drug interactions, or result in disorders of endobiotic metabolism. Most of the current machine learning methods predicting the inhibition of drug metabolizing enzymes neglect protein structure and dynamics, both being essential for the recognition of various substrates and inhibitors. We performed molecular dynamics simulations on a homology model of the human UGT1A1 structure containing both the cofactor- (UDP-glucuronic acid) and substrate-binding domains to explore UGT conformational changes. Then, we created models for the prediction of UGT1A1 inhibitors by integrating information on UGT1A1 structure and dynamics, interactions with diverse ligands, and machine learning. These models can be helpful for further prediction of drug-drug interactions of drug candidates and safety treatments.Graphical abstractDisplay OmittedHighlights•UGTs are responsible for 35% of the phase II drug metabolism reactions•We created machine learning models for prediction of UGT1A1 inhibitors•Our simulations suggested key residues of UGT1A1 involved in the substrate bindingDrugs; Computational chemistry; Bioinformatics; Artificial intelligence