Acetylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B: An experimental and computational study |
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Affiliation: | 1. Department of Electrical and Electronics Engineering, Atılım University, Ankara 06836, Turkey;2. Department of Chemistry, University of California Davis, One Shields Avenue, Davis, CA 95616, USA;3. Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz 55128, Germany;4. IKERBASQUE, Basque Foundation for Science, Bilbao, E-48011, Spain;1. Yale-NUS College, Singapore 138527, Singapore;2. Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore;3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore;4. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore |
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Abstract: | The chemo- and enantioselectivity of the Candida antarctica lipase B (CalB)-catalyzed acetylation reaction of (R,S)-propranolol using vinyl acetate as acyl donor and toluene as organic solvent was studied. Because of the poor solubility of propranolol in toluene small quantities of methanol were added as cosolvent. The effects of the propranolol/vinyl acetate ratio, the enzyme purification procedure and the methanol concentration on the reaction were investigated. The reactions occurring in the system were quantitatively investigated using 1H and 13C NMR spectroscopy. The major reactions were the hydrolysis and alcoholysis of vinyl acetate, as a consequence of the presence of residual water and methanol in the reaction medium. Furthermore, the NMR analysis confirmed that O-acetyl-propranolol was formed exclusively. The reaction was also found to be enantioselective favoring the faster transformation of the R-propranolol. In addition to the experiments, molecular modeling was used to study the formation of the reactive Michaelis complexes between propranolol and acetylated CalB, using a combined molecular docking and molecular dynamics (MD) procedure. Only for the O-acetylation we found binding modes of the substrate leading to formation of the product, which explains the experimentally observed chemoselectivity of CalB. |
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Keywords: | Chiral resolution Molecular modeling NMR spectroscopy Chemoselectivity |
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