Computational studies of epoxide hydrolase-catalyzed ring-opening reactions

Chiral 1,2-amino alcohols are motifs widely present in different high valuable biologically active compounds. Many synthetic and enzymatic routes have been developed for producing optically active amino alcohols starting from diols, ketones, and esters. Enantiopure diols and epoxide substrates have shown to be highly versatile intermediates in organic synthesis, in particular these compounds have received attention due to their role as key chiral precursors to access enantiopure beta-blocker drugs, such as alprenolol and propranolol. These compounds have been traditionally prepared starting from alkene and epoxide substrates by using chemical catalysts. Nevertheless, epoxide hydrolases (EHs) offers an alternative and attractive route for the production of such compounds just starting from cheap and easy-to-access racemic mixtures of epoxides. In short, this is because some EHs have the ability to distinguish between different substrate enantiomers, while many others can preferentially attack one carbon atom of the epoxide ring moiety. In the present thesis, the EH that caught our attention was the one from Bacillus megaterium (BmEH), mainly due to its ability to accept bulkier substrates such as naphthyl glycidyl ether, and also for displaying the (R) selectivity toward aryl glycidyl ethers, which is opposite to that selectivity observed in many other similar EHs. Based on this information, the thesis have been focused computational studies of the reaction mechanism of BmEH, as well as the exploration of its conformational dynamics in order to understand the origins and the main factors having an influence on its enzymatic activity ​
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