ArticleJournal of cheminformatics2020
Predicting liver cytosol stability of small molecules.
Article in Journal of cheminformatics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Cross-Species Multitask Learning with Molecular and ADME Descriptors for Liver Microsomal Metabolic Stability.Computational and structural biotechnology journal · 2026Article
- Advancements in forecasting liver cytosol metabolic stability: a comprehensive update on machine learning predictive models.Bioinformatics advances · 2026Article
- Transformation of a Potent C9-Substituted Phenylmorphan into MOR Partial Agonists with Improvement of Metabolic Stability: An In Vitro, In Vivo, and In Silico Study.ACS chemical neuroscience · 2025Article
- Machine learning-driven generation and screening of potential ionic liquids for cellulose dissolution.Journal of cheminformatics · 2025Article
- Developing Robust Human Liver Microsomal Stability Prediction Models: Leveraging Inter-Species Correlation with Rat Data.Pharmaceutics · 2024Article
- MS-BACL: enhancing metabolic stability prediction through bond graph augmentation and contrastive learning.Briefings in bioinformatics · 2024Article
- Artificial Intelligence in ADME Property Prediction.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Consideration of vendor-related differences in hepatic metabolic stability data to optimize early ADME screening in drug discovery.SLAS discovery : advancing life sciences R & D · 2024Article
- In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Article
- CMMS-GCL: cross-modality metabolic stability prediction with graph contrastive learning.Bioinformatics (Oxford, England) · 2023Article
- Development and validation of PAMPA-BBB QSAR model to predict brain penetration potential of novel drug candidates.Frontiers in pharmacology · 2023Article
- Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis.Journal of medicinal chemistry · 2022Article
- Using in vitro ADME data for lead compound selection: An emphasis on PAMPA pH 5 permeability and oral bioavailability.Bioorganic & medicinal chemistry · 2022Review
- Preclinical Pharmacokinetics andFrontiers in pharmacology · 2022Article
- How can SHAP values help to shape metabolic stability of chemical compounds?Journal of cheminformatics · 2021Article
- NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization.Journal of pharmaceutical and biomedical analysis · 2021Article
- Retrospective assessment of rat liver microsomal stability at NCATS: data and QSAR models.Scientific reports · 2020Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Over the last few decades, chemists have become skilled at designing compounds that avoid cytochrome P (CYP) 450 mediated metabolism. Typical screening assays are performed in liver microsomal fractions and it is possible to overlook the contribution of cytosolic enzymes until much later in the drug discovery process. Few data exist on cytosolic enzyme-mediated metabolism and no reliable tools are available to chemists to help design away from such liabilities. In this study, we screened 1450 compounds for liver cytosol-mediated metabolic stability and extracted transformation rules that might help medicinal chemists in optimizing compounds with these liabilities. In vitro half-life data were collected by performing in-house experiments in mouse (CD-1 male) and human (mixed gender) cytosol fractions. Matched molecular pairs analysis was performed in conjunction with qualitative-structure activity relationship modeling to identify chemical structure transformations affecting cytosolic stability. The transformation rules were prospectively validated on the test set. In addition, selected rules were validated on a diverse chemical library and the resulting pairs were experimentally tested to confirm whether the identified transformations could be generalized. The validation results, comprising nearly 250 library compounds and corresponding half-life data, are made publicly available. The datasets were also used to generate in silico classification models, based on different molecular descriptors and machine learning methods, to predict cytosol-mediated liabilities. To the best of our knowledge, this is the first systematic in silico effort to address cytosolic enzyme-mediated liabilities.
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Registered trials
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