Design of configuration-restricted triazolylated β-d-ribofuranosides: a unique family of crescent-shaped RNase A inhibitors
Autor: | Ashrukana Das, Swagata Dasgupta, Tanmaya Pathak |
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Rok vydání: | 2020 |
Předmět: |
biology
Stereochemistry RNase P Hydrogen bond Ribose Organic Chemistry Molecular Conformation Active site Ribonuclease Pancreatic Biochemistry chemistry.chemical_compound chemistry Docking (molecular) Drug Design biology.protein Molecule Moiety Animals Cattle Ribonuclease Physical and Theoretical Chemistry Enzyme Inhibitors |
Zdroj: | Organicbiomolecular chemistry. 18(32) |
ISSN: | 1477-0539 |
Popis: | Seven new carbohydrate–bistriazole hybrid molecules were designed taking into consideration the crescent shaped active site of ribonuclease A (RNase A). In this case, the β-D-ribofuranose structure was used as the basic building unit; both the C1 and C4 arms protruding out towards the β-face of the tetrahydrofuran moiety of the ribose sugar provided an overall “U” shape to the basic building block. Several combinations of bistriazole moieties were constructed on the two arms of this basic building block. These mono- and/or bis-substituted 1,2,3-triazole units were linked to acidic functional groups because of the overall basic nature of the hydrolytic site of RNase A. All these compounds were efficient competitive inhibitors of RNase A with inhibition constants (Ki) in the micromolar range. In contrast to the carboxylic acid-modified hybrid molecules, molecules carrying sulfonic acids were found to be more potent because of the stronger interactions with the positively charged active site. The most efficient inhibitor of the series was the disulfonic acid-functionalized carbohydrate-bis-triazole hybrid molecule. Docking studies disclosed that the molecule, because of its well defined “U” shape with flexible arms, fits effectively in the active site; moreover, in all cases, besides the acid groups, the triazole and sugar rings also actively participated in creating the hydrogen bonding network in the cavity of the enzyme active site. |
Databáze: | OpenAIRE |
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