Nanomolar inhibition of human OGA by 2-acetamido-2-deoxy-d-glucono-1,5-lactone semicarbazone derivatives
| Autor: | Mariann Kiss, Erna Szabó, Boglárka Bocska, István Timári, Joseph Hayes, Conceicao Piedade Fernandes, Teréz Barna, Luu Thanh Sinh, László Somsák |
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| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
Hyaluronoglucosaminidase Thio Molecular Dynamics Simulation Ligands 01 natural sciences Serine Lactones Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Antigens Neoplasm Drug Discovery Hydrolase Humans Moiety Transferase Enzyme Inhibitors Threonine Semicarbazone Histone Acetyltransferases 030304 developmental biology Semicarbazones Pharmacology chemistry.chemical_classification 0303 health sciences Binding Sites Protein Stability 010405 organic chemistry Chemistry B230 Organic Chemistry General Medicine Recombinant Proteins 0104 chemical sciences Kinetics Quantum Theory Lactone Protein Binding |
| Zdroj: | European Journal of Medicinal Chemistry. 223:113649 |
| ISSN: | 0223-5234 |
| Popis: | O-GlcNAcylation is a dynamic post-translational modification mediated by O-linked β-N-acetylglucosamine transferase (OGT) and O-GlcNAc hydrolase (OGA), that adds or removes a single β-N-acetylglucosamine (GlcNAc) moiety to or from serine/threonine residues of nucleocytosolic and mitochondrial proteins, respectively. The perturbed homeostasis of O-GlcNAc cycling results in several pathological conditions. Human OGA is a promising therapeutic target in diseases where aberrantly low levels of O-GlcNAc are experienced, such as tauopathy in Alzheimer's disease. A new class of potent OGA inhibitors, 2-acetamido-2-deoxy-D-glucono-1,5-lactone (thio)semicarbazones, have been identified. Eight inhibitors were designed and synthesized in five steps starting from d-glucosamine and with 15–55% overall yields. A heterologous OGA expression protocol with strain selection and isolation has been optimized that resulted in stable, active and full length human OGA (hOGA) isomorph. Thermal denaturation kinetics of hOGA revealed environmental factors affecting hOGA stability. From kinetics experiments, the synthesized compounds proved to be efficient competitive inhibitors of hOGA with K i -s in the range of ∼30–250 nM and moderate selectivity with respect to lysosomal β-hexosaminidases. In silico studies consisting of Prime protein-ligand refinements, QM/MM optimizations and QM/MM-PBSA binding free energy calculations revealed the factors governing the observed potencies, and led to design of the most potent analogue 2-acetamido-2-deoxy-D-glucono-1,5-lactone 4-(2-naphthyl)-semicarbazone 6g (K i = 36 nM). The protocol employed has applications in future structure based inhibitor design targeting OGA. |
| Databáze: | OpenAIRE |
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