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Fragment-based drug design facilitated by dynamic combinatorial chemistry and NMR spectroscopy

Kroon, P.C. (2015) Fragment-based drug design facilitated by dynamic combinatorial chemistry and NMR spectroscopy. Master's Thesis / Essay, Chemistry.

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Drug development is a challenging process, which often fails. To ameliorate this, we attempted to develop an efficient methodology for fragment‐based drug design based on dynamic combinatorial chemistry and NMR spectroscopy. To this end, two libraries were designed based on crystallographic data from the group of Klebe for the model protein endothiapepsin using computer aided modelling. The designed compounds all feature an acylhdyrazone linker and at least one fluorine atom. The first library was discarded due to problems with the synthesis. The second library was analysed using quantitative 19F‐NMR and 1H‐STD‐NMR spectroscopy, using trifluoroacetic acid as an internal reference for the fluorine NMR spectra. No binding compounds could be identified, even though one of the compounds was a known binder. It is hypothesised this is due to the trifluoroacetic acid since the 1H‐STD‐NMR spectrometry also produced no results. However, it could be concluded that 19F‐NMR spectrometry provides better peak resolution with little loss of sensitivity compared to 1H‐NMR spectrometry when analysing mixtures; and that STD‐NMR requires far less protein than regular NMR spectroscopy for analysing templated DCLs.

Item Type: Thesis (Master's Thesis / Essay)
Degree programme: Chemistry
Thesis type: Master's Thesis / Essay
Language: English
Date Deposited: 15 Feb 2018 08:03
Last Modified: 15 Feb 2018 08:03

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