Computational cytochrome P450 mediated metabolism and virtual screening
Julkaistu sarjassa
JYU dissertationsTekijät
Päivämäärä
2021Tekijänoikeudet
© The Author & University of Jyväskylä
Computational drug design aids to lower the costs and amount of experimental
testing required to identify potent bioactive lead molecules for biological target
macromolecules, usually proteins. Computational prediction and analysis of
cytochrome P450 (CYP) enzyme mediated metabolism can be used to assess
bioavailability, potential drug-drug interactions and metabolic reaction
products, and thus to abandon or re-design potentially harmful lead compounds,
improve drug candidate bioavailability, and to design prodrugs that are
activated at a metabolic event. Virtual screening (VS), in turn, is used to find
novel bioactive compounds from a large virtual molecular database, filtering the
number of compounds subjected to experimental testing. In this doctoral thesis,
protein structure-based methods were utilized for computational prediction and
analysis of CYP metabolism and VS. Metrics of binding free energy, ligand
stability and accessibility for metabolic reaction in the CYP ligand binding site
are suggested for future prediction and analysis protocols of CYP metabolism
using molecular dynamics (MD) simulations. Using these metrics and expert
analysis, MD simulations offered rationalization of catalytic and inhibitory
activities of novel CYP ligands. Novel profluorescent tool molecules are
presented for experimental CYP assays. Molecular modelling and docking aided
to identify the most potent target CYP enzymes for these compounds. Moreover,
further MD simulations suggested an essential role of water interactions and
access channel composition for the fluorescent catalysis of the tool molecules in
the CYP1 enzyme family. Finally, a workflow and practical discussion for a
priorly developed protein binding site negative image-based (NIB) VS
methodology, Panther, is presented. The presented results, computational
methods, and tool molecules offer potent tools for drug development and ideas
for the further development of the methods.
Keywords: Cytochrome P450; Computer-aided drug design; Site of metabolism
prediction; Virtual screening.
...
Julkaisija
Jyväskylän yliopistoISBN
978-951-39-8496-0ISSN Hae Julkaisufoorumista
2489-9003Julkaisuun sisältyy osajulkaisuja
- Artikkeli I: Juvonen R.O., Kuusisto M., Fohrgrup C., Pitkänen M.H., Nevalainen T.J., Auriola S., Raunio H., Pasanen M. & Pentikäinen O.T. (2016). Inhibitory effects and oxidation of 6-methylcoumarin, 7-methylcoumarin and 7- formylcoumarin via human CYP2A6 and its mouse and pig orthologous enzymes. Xenobiotica 46: 14–24. DOI: 10.3109/00498254.2015.1048327
- Artikkeli II: Ahinko, M., Niinivehmas, S., Jokinen, E., & Pentikäinen, O. (2019). Suitability of MMGBSA for the selection of correct ligand binding modes from docking results. Chemical Biology and Drug Design, 93 (4), 522-538. DOI: 10.1111/cbdd.13446
- Artikkeli III: Juvonen, R. O., Ahinko, M., Huuskonen, J., Raunio, H., & Pentikäinen, O. (2019). Development of New Coumarin-Based Profluorescent Substrates for Human Cytochrome P450 Enzymes. Xenobiotica, 49 (9), 1015-1024. DOI: 10.1080/00498254.2018.1530399
- Artikkeli IV: Juvonen R.O., Ahinko M., Huuskonen J., Raunio H. & Pentikäinen O.T. Substrate selectivity of coumarin derivatives by human CYP1 enzymes: in vitro enzyme kinetics and in silico modelling. Manuscript.
- Artikkeli V: Ahinko, M., Kurkinen, S., Niinivehmas, S., Pentikäinen, O., & Postila, P. (2019). A Practical Perspective : The Effect of Ligand Conformers on the Negative Image-Based Screening. International Journal of Molecular Sciences, 20 (11), 2779. DOI: 10.3390/ijms20112779
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