Effect of the acyl-group length on the chemoselectivity of the lipase-catalyzed acylation of propranolol-a computational study
| Autor: | Martha C. Daza, Markus Doerr, Alexander Romero |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Stereochemistry Protein Conformation Acylation Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Catalysis Enzyme catalysis Substrate Specificity Inorganic Chemistry Fungal Proteins chemistry.chemical_compound Nucleophile 0103 physical sciences Physical and Theoretical Chemistry Chemoselectivity Lipase 010304 chemical physics biology Basidiomycota Organic Chemistry Computational Biology biology.organism_classification Propranolol 0104 chemical sciences Computer Science Applications Kinetics Computational Theory and Mathematics chemistry Docking (molecular) biology.protein lipids (amino acids peptides and proteins) Candida antarctica Acyl group |
| Zdroj: | Journal of molecular modeling. 27(7) |
| ISSN: | 0948-5023 |
| Popis: | The selective N-acylation of 1,2-amino alcohols has been proposed to occur through the proton shuttle mechanism. However, the O-acetylation of propranolol catalyzed by Candida antarctica lipase B is an exception. We investigated the relation between the chemoselectivity of this reaction and the acyl group length. For this purpose, we compared the acyl groups: ethanoyl, butanoyl, octanoyl, and hexadecanoyl. We studied the Michaelis complexes between serine-acylated Candida antarctica lipase B and propranolol, employing a computational approach that involved sampling Michaelis complex conformations through ensemble docking plus consensus scoring and molecular dynamics simulations. The conformations were then classified as near attack conformations for acylation of the amino or hydroxy group. The relative populations of these two classes of conformations were found to be consistent with the experimentally observed chemoselective O-acetylation. We predict that increasing the length of the hydrocarbon chain of the acyl group will cause O-acylation to be unfavorable with respect to N-acylation. The nucleophilic attack of propranolol to the acylated lipase was found to be more favorable through the classical mechanism when compared with the proton shuttle mechanism. |
| Databáze: | OpenAIRE |
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