Insights into the pharmacophore-based 3D-QSAR modeling, molecular dynamics simulation studies of certain dihydroxy pyrrolidine/piperidine and aza-flavanone derivatives as α-glucosidase inhibitors

Diabetes mellitus is a metabolic disorder and causes relentless health problems, morbidity and mortality to human population around the globe. Acarbose, voglibose and miglitol are some of the eminent glucosidase inhibitors used to control diabetes mellitus. Even though, these eminent and clinically accepted inhibitor's usage was limited because of their side effects. Consequently, there still is a need to extend a safer therapy for diabetes mellitus. Current research focuses on small molecule discovery with an aim to treat a number of diseases and disorders through target-based action. Especially, dihydroxy pyrrolidine/piperidine and aza-flavanones are pharmacologically significant scaffolds in drug discovery research and are also well evaluated for their alpha-glucosidase inhibitory activity. In the present study conducted, an attempt was made to explore the pharmacophoric features of several alpha-glucosidase inhibitors through computational approach. An atom-based 3D-QSAR technique was utilized to approve the features that are obtained from 76 compounds. Spatial arrangement and structural features required for a-glucosidase inhibition was analyzed through the developed 3D-QSAR models. A 3D model structure was reproduced for target protein to assess the binding properties of the ligands with protein through homology modelling techniques. Molecular dynamics simulations were performed to understand the conformational fluctuations and stability of ligands at the active pocket of the enzyme. In future, these in silico results will aid the discovery of a-glucosidase inhibitors with good pharmacophoric features and potency. (C) 2020 Published by Elsevier B.V.

Automated summary

This study aims to explore the pharmacophoric features of several alpha-glucosidase inhibitors through computational approach, utilizing an atom-based 3D-QSAR technique to analyze the spatial arrangement and structural features required for alpha-glucosidase inhibition. A 3D model structure was reproduced for the target protein to assess the binding properties of the ligands with the protein through homology modelling techniques. Molecular dynamics simulations were performed to understand the conformational fluctuations and stability of ligands at the active pocket of the enzyme. These in silico results will aid in the discovery of alpha-glucosidase inhibitors with good pharmacophoric features and potency.