Strategy for Designing Selective Lysosomal Acid ?-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity.

ABSTRACT: Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit ?-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between ?-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid ?-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of ?-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC50 value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the ?-1-C-alkyl chain. It is noteworthy that ?-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) ?-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each ?-glucosidase may lead to the creation of more selective and practically useful inhibitors.

SUBMITTER: Kato A 

PROVIDER: S-EPMC7357040 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature