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• W1594799219 abstract "The assessment of ADME properties and metabolic behavior of a drug is central in drug discovery and drug design. The main target for studies of metabolic properties is the Cytochrome P450 (CYP), which is responsible for the metabolism of a majority of drugs on the market and consequently also involved in many drug-drug interactions. Examples of information and tools that could guide drug design towards favorable metabolic properties are structural information of the CYPs, affinity and selectivity towards the CYPs and the site of metabolism (SOM). The present work was initiated to use experimental and computational tools to study the affinity and selectivity for two of the most important isoenzymes, CYP2D6 and CYP3A4, and highlight the benefit of combining different approaches and assays to understand the metabolic properties of a drug. A novel computational approach resulting in an assessment of enzyme-ligand interaction patterns were successfully used for a comparison of different 3D-structures in order to highlight discriminative amino acid residues. This method could also offer an identification of important interactions when understanding affinity and selectivity for an enzyme. In order to explore affinity and selectivity factors in CYP3A4 and CYP2D6 mediated metabolism two compounds were selected for an experimental evaluation of the catalytic properties of the enzyme. Based on the results from different in vitro assays it could be concluded that CYP3A4 was more unselective, producing metabolites as a result of orientations presenting many different parts of the molecules to the heme. CYP2D6 on the other hand showed more restricted binding modes. The combined information from inhibition studies and metabolite identification also gave indications on productive and non-productive binding modes in the two enzymes. With further exploration of CYP2D6, and its pharmacophore, N-dealkylation and the effect of blocking the SOM in CYP2D6 substrates were studied. These results were in agreement with the previously stated pharmacophore and also showed that the SOM for these substrates could be successfully assigned with a ligand-based approach, which could also be used to assign selectivity for CYP2D6. Key information, in designing compounds towards preferable metabolic properties, is obtained from metabolite identification or SOM determinations. I order to enhance metabolite identification a semi-automated software was tested that assigned the metabolite structure from MS raw data with high success rate. This could consequently be beneficial for drug design in that it enables a high throughput of metabolite identification data. During the course of these work important aspects to consider in drug design has been observed, e.g. improving metabolic stability by blocking soft spots tend to result in CYP inhibition. Instead of blocking soft spots the affinity for an enzyme could be diminished and this could be guided by the computational approach used in the first project. In summary, the combined knowledge from in vitro and in silico tools could be beneficial for the understanding of the metabolic behavior of a drug." @default.
• W1594799219 created "2016-06-24" @default.
• W1594799219 creator A5084826801 @default.
• W1594799219 date "2010-09-02" @default.
• W1594799219 modified "2023-09-23" @default.
• W1594799219 title "Experimental and computational investigation of affinity and selectivity factors in CYP2D6 and CYP3A4 mediated metabolism" @default.
• W1594799219 cites W1498584605 @default.
• W1594799219 cites W1498652161 @default.
• W1594799219 cites W1510717844 @default.
• W1594799219 cites W1551078098 @default.
• W1594799219 cites W1589803282 @default.
• W1594799219 cites W1604793684 @default.
• W1594799219 cites W1832059623 @default.
• W1594799219 cites W1889740990 @default.
• W1594799219 cites W1895993106 @default.
• W1594799219 cites W1951469402 @default.
• W1594799219 cites W1955010122 @default.
• W1594799219 cites W1963761471 @default.
• W1594799219 cites W1965612834 @default.
• W1594799219 cites W1968833927 @default.
• W1594799219 cites W1971223189 @default.
• W1594799219 cites W1971863374 @default.
• W1594799219 cites W1975206909 @default.
• W1594799219 cites W1977444218 @default.
• W1594799219 cites W1978524270 @default.
• W1594799219 cites W1978896527 @default.
• W1594799219 cites W1982694126 @default.
• W1594799219 cites W1983569709 @default.
• W1594799219 cites W1986914000 @default.
• W1594799219 cites W1987924005 @default.
• W1594799219 cites W1992187482 @default.
• W1594799219 cites W1992475241 @default.
• W1594799219 cites W1992581513 @default.
• W1594799219 cites W1993047099 @default.
• W1594799219 cites W1996286663 @default.
• W1594799219 cites W2000051743 @default.
• W1594799219 cites W2002173485 @default.
• W1594799219 cites W2003946693 @default.
• W1594799219 cites W2005263430 @default.
• W1594799219 cites W2006252190 @default.
• W1594799219 cites W2008937789 @default.
• W1594799219 cites W2011969256 @default.
• W1594799219 cites W2012271559 @default.
• W1594799219 cites W2012370023 @default.
• W1594799219 cites W2014240726 @default.
• W1594799219 cites W2014919794 @default.
• W1594799219 cites W2015728154 @default.
• W1594799219 cites W2018361595 @default.
• W1594799219 cites W2021232512 @default.
• W1594799219 cites W2021474803 @default.
• W1594799219 cites W2023736833 @default.
• W1594799219 cites W2024059620 @default.
• W1594799219 cites W2026185422 @default.
• W1594799219 cites W2026282976 @default.
• W1594799219 cites W2032865420 @default.
• W1594799219 cites W2033183112 @default.
• W1594799219 cites W2034566612 @default.
• W1594799219 cites W2037431844 @default.
• W1594799219 cites W2037641376 @default.
• W1594799219 cites W2039249350 @default.
• W1594799219 cites W2041121356 @default.
• W1594799219 cites W2055605433 @default.
• W1594799219 cites W2060180669 @default.
• W1594799219 cites W2064799851 @default.
• W1594799219 cites W2070098436 @default.
• W1594799219 cites W2080653934 @default.
• W1594799219 cites W2089353933 @default.
• W1594799219 cites W2089468765 @default.
• W1594799219 cites W2092019850 @default.
• W1594799219 cites W2097100227 @default.
• W1594799219 cites W2104180764 @default.
• W1594799219 cites W2105587896 @default.
• W1594799219 cites W2106109834 @default.
• W1594799219 cites W2106195907 @default.
• W1594799219 cites W2116184147 @default.
• W1594799219 cites W2118868944 @default.
• W1594799219 cites W2121960436 @default.
• W1594799219 cites W2122368088 @default.
• W1594799219 cites W2127294029 @default.
• W1594799219 cites W2130983257 @default.
• W1594799219 cites W2131414900 @default.
• W1594799219 cites W2131759299 @default.
• W1594799219 cites W2132763051 @default.
• W1594799219 cites W2134483287 @default.
• W1594799219 cites W2144860443 @default.
• W1594799219 cites W2145651065 @default.
• W1594799219 cites W2147337743 @default.
• W1594799219 cites W2148849061 @default.
• W1594799219 cites W2153467586 @default.
• W1594799219 cites W2153538952 @default.
• W1594799219 cites W2153834789 @default.
• W1594799219 cites W2154598050 @default.
• W1594799219 cites W2156273681 @default.
• W1594799219 cites W2156423252 @default.
• W1594799219 cites W2159425682 @default.
• W1594799219 cites W2162575052 @default.
• W1594799219 cites W2163818982 @default.
• W1594799219 cites W2204075485 @default.
• W1594799219 hasPublicationYear "2010" @default.
• W1594799219 type Work @default.

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