Validating ADME QSAR Models Using Marketed Drugs
| Autor: | Noel Southall, Jordan Williams, Ewy Mathé, Jorge Neyra, Vishal B. Siramshetty, Xin Xu, Ðắc-Trung Nguyễn, Pranav Shah |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
Quantitative structure–activity relationship media_common.quotation_subject Quantitative Structure-Activity Relationship Computational biology 01 natural sciences Biochemistry Models Biological Analytical Chemistry 03 medical and health sciences Drug Discovery Animals Translational Science Biomedical 030304 developmental biology media_common ADME 0303 health sciences Chemistry National Center for Advancing Translational Sciences (U.S.) United States 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Pharmaceutical Preparations Molecular Medicine Biotechnology |
| Zdroj: | SLAS discovery : advancing life sciences RD. 26(10) |
| ISSN: | 2472-5560 |
| Popis: | Problems with drug ADME are responsible for many clinical failures. By understanding the ADME properties of marketed drugs and modeling how chemical structure contributes to these inherent properties, we can help new projects reduce their risk profiles. Kinetic aqueous solubility, the parallel artificial membrane permeability assay (PAMPA), and rat liver microsomal stability constitute the Tier I ADME assays at the National Center for Advancing Translational Sciences (NCATS). Using recent data generated from in-house lead optimization Tier I studies, we update quantitative structure-activity relationship (QSAR) models for these three endpoints and validate in silico performance against a set of marketed drugs (balanced accuracies range between 71% and 85%). Improved models and experimental datasets are of direct relevance to drug discovery projects and, together with the prediction services that have been made publicly available at the ADME@NCATS web portal (https://opendata.ncats.nih.gov/adme/), provide important tools for the drug discovery community. The results are discussed in light of our previously reported ADME models and state-of-the-art models from scientific literature. |
| Databáze: | OpenAIRE |
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