A Unified Proteochemometric Model for Prediction of Inhibition of Cytochrome P450 Isoforms
Open accessAbstract
A unified proteochemometric (PCM) model for the prediction of the ability of drug-like chemicals to inhibit five major drug metabolizing CYP isoforms (i.e. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was created and made publicly available under the Bioclipse Decision Support open source system at www.cyp450model.org. In regards to the proteochemometric modeling we represented the chemical compounds by molecular signature descriptors and the CYP-isoforms by alignment-independent description of composition and transition of amino acid properties of their protein primary sequences. The entire training dataset contained 63 391 interactions and the best PCM model was obtained using signature descriptors of height 1, 2 and 3 and inducing the model with a support vector machine. The model showed excellent predictive ability with internal AUC = 0.923 and an external AUC = 0.940, as evaluated on a large external dataset. The advantage of PCM models is their extensibility making it possible to extend our model for new CYP isoforms and polymorphic CYP forms. A key benefit of PCM is that all proteins are confined in one single model, which makes it generally more stable and predictive as compared with single target models. The inclusion of the model in Bioclipse Decision Support makes it possible to make virtual instantaneous predictions (∼100 ms per prediction) while interactively drawing or modifying chemical structures in the Bioclipse chemical structure editor.
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Lapins et al. applied PCM to predict inhibition of five major drug metabolizing isoforms of cytochrome P450.
“In other study, Lapins et al.119 applied PCM method to predict inhibition of five major drug metabolizing isoforms of cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) by drug-like compounds.”
From QSAR without borders (2020) · cites this paper as [119]
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Muratov, E. N., Bajorath, J., Sheridan, R. P., Tetko, I. V., Filimonov, D., Poroikov, V., Oprea, T. I., Baskin, I. I., Varnek, A., Roitberg, A., et al. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00098a · Cited by 913 · see citing works
- Authors
- Lapins, M., Worachartcheewan, A., Spjuth, O., Georgiev, V., Prachayasittikul, V., Nantasenamat, C., & Wikberg, J. E. S.
- Affiliations
- Uppsala University (SE)
- Mahidol University (TH)
- Corresponding author
- Wikberg, Jarl E. S.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-17
- Volume
- 8
- Issue
- 6
- Pages
- e66566
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3684587
- OpenAlex
- W2118339791
- Cited by
- 46
- References
- 32
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 6 · 2013: 1
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Mahidol University (C0610701)
- Office of the Higher Education Commission
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- proteochemometrics, cytochrome P450 inhibition, CYP isoforms, drug metabolism, molecular descriptors, amino acid composition, support vector machine, virtual screening, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP1A2
- MeSH terms
- Cytochrome P-450 Enzyme System, Isoenzymes, Models, Chemical, Pharmacokinetics, Area Under Curve, Support Vector Machine, Cytochrome P-450 Enzyme Inhibitors
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