Rational Design of Novel Inhibitors of α-Glucosidase: An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening

alpha-Glucosidase is considered a prime drug target for Diabetes Mellitus and its inhibitors are used to delay carbohydrate digestion for the treatment of diabetes mellitus. With the aim to design alpha-glucosidase inhibitors with novel chemical scaffolds, three folds ligand and structure based virtual screening was applied. Initially linear quantitative structure activity relationship (QSAR) model was developed by a molecular operating environment (MOE) using a training set of thirty-two known inhibitors, which showed good correlation coefficient (r(2) = 0.88), low root mean square error (RMSE = 0.23), and cross-validated correlation coefficient r(2) (q(2) = 0.71 and RMSE = 0.31). The model was validated by predicting the biological activities of the test set which depicted r(2) value of 0.82, indicating the robustness of the model. For virtual screening, compounds were retrieved from zinc is not commercial (ZINC) database and screened by molecular docking. The best docked compounds were chosen to assess their pharmacokinetic behavior. Later, the alpha-glucosidase inhibitory potential of the selected compounds was predicted by their mode of binding interactions. The predicted pharmacokinetic profile, docking scores and protein-ligand interactions revealed that eight compounds preferentially target the catalytic site of alpha-glucosidase thus exhibit potential alpha-glucosidase inhibition in silico. The alpha-glucosidase inhibitory activities of those Hits were predicted by QSAR model, which reflect good inhibitory activities of these compounds. These results serve as a guidelines for the rational drug design and development of potential novel anti-diabetic agents.

Automated summary

The study aimed to design novel alpha-glucosidase inhibitors using multiple methods including QSAR modeling, virtual screening, and molecular docking. Results demonstrated that certain compounds exhibit potential inhibition of alpha-glucosidase, guiding the rational design and development of new anti-diabetic agents.