Title:Studies on α-Glucosidase Inhibitors Development: Magic Molecules for the Treatment of Carbohydrate Mediated Diseases
Volume: 12
Issue: 8
Author(s): N. S.H.N. Moorthy, M. J. Ramos and P. A. Fernandes
Affiliation:
Keywords:
α-Glucosidases, HIV, QSAR, hydrophobicity, vdW surface area.
Abstract: α-Glucosidase (EC 3.2.1.20) enzyme belongs to the glycosidase family enzymes, cleave the glycosidic bond of
the oligosaccharides that liberate glucose and its inhibition retards the carbohydrate digestion. In the present review, we
have discussed the structural features of different α-glucosidase inhibitors (small molecules) responsible for the inhibitory
activities. The reported computational studies including, QSAR, pharmacophore modelling, homology models, docking
(with analogs enzymes), etc revealed that the topological, electronic and hydrophobicity properties determine the
interactions of those molecules. The aromatic substituents connected with flexible bonds in the molecules have significant
effect on the interactions, which may due to the presence of aromatic amino acid residues in the active site. The reported
homology modelled and other analogs enzymes (enzymes of other species) also confirmed the existence of aromatic
residue (amino acids) especially, histidine, phenylalanine and tyrosine in their active site along with the polar (glutamic
and aspartic acids) residues. Multiple sequence alignments of the α-glucosidase enzymes (from different species)
described that the abovementioned amino acid residues are present in the active site of all the studied enzymes. Recently,
Celgosivir (MIGENIX Inc) is an oral prodrug of the natural product castanospermine used for the treatment of HCV
infection by inhibiting α-glucosidase I. BMN-701 is an α-glucosidase inhibitors in the phase I pipeline (BioMarine) for
the treatment of Pompe diseases. CKD-711 and CKD-711a are aminooligosaccharide α-glucosidase inhibitors and the in
vitro study of CKD-711 showed similar effects to acarbose on porcine intestinal maltase and sucrase (IC50s of 2.5 and 0.5
μg/ml). This review also concluded that many α-glucosidases inhibitors obtained from natural products are used for the
treatment of various carbohydrate mediated diseases. The structural analysis of these synthetic and natural derivatives
guide for the development of novel semisynthetic/synthetic α-glucosidase inhibitors with free of toxicities.
