Systematic Structure-Activity Study on Potential Chaperone Lead Compounds for Acid α-Glucosidase
| Autor: | Elina Kuokkanen, Heidi Repo, Pirkko Heikinheimo, Chiara Bruckmann, Henri Xhaard |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular congenital hereditary and neonatal diseases and abnormalities Glycoconjugate Biochemistry Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Drug Discovery Humans Glycoside hydrolase Homology modeling Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology Glycogen Storage Disease Type II Organic Chemistry ta1182 nutritional and metabolic diseases Active site alpha-Glucosidases Ligand (biochemistry) Small molecule Recombinant Proteins Enzyme chemistry Drug Design Chaperone (protein) biology.protein Molecular Medicine Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | ChemMedChem. 7:1943-1953 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201200309 |
| Popis: | Acid α-glucosidase (GAA) is a lysosomal enzyme and a pharmacological target for Pompe disease, an inherited lysosomal storage disorder (LSD). An emerging treatment for LSDs is the use of pharmacological chaperones, small molecules that enhance total cellular activity of the target lysosomal protein. We have systematically studied thirteen inhibitors, which provide good lead compounds for the development of GAA chaperones. We have verified binding on GAA at low and neutral pH, mapping the range of pH during transport to lysosomes. These ligands inhibit GAA competitively and reversibly, and a few of the compounds show higher molecular stabilisation capacity than would be expected from their binding affinity. These molecules also increase lysosomal localisation of GAA variants in cells. In order to understand the specific molecular mechanism of the interactions, we docked the compounds to a homology model of the human GAA. Three factors contribute to the tightness of binding. Firstly, well-positioned hydroxy groups are essential to orient the ligand and make the binding specific. Secondly, the open nature of the GAA active site allows both large and small ligands to bind. The third and most important binding determinant is the positive charge on the ligand, which is neutralised by Asp 518 or Asp 616 on GAA. Our study creates a firm basis for the design of drugs to treat Pompe disease, as it provides a comparable study of the ligand properties. Our analysis suggests a useful drug design framework for specific pharmacological chaperones for human GAA. |
| Databáze: | OpenAIRE |
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