Abstract
Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.
Highlights
Several glucosidases catalyze the cleavage of glycosidic bonds in oligosaccharides or glycoconjugates and release glucose from the non-reducing end of the oligosaccharide chain. a-glucosidase (EC. 3.2.1.20; a-glucosidase glucohydrolase) is an enzyme that catalyzes the cleavage of glycosidic bond in maltose [1]
Our report on non-glycosidic derivatives demonstrated that readily accessible achiral (E)-1-phenyl-3-(4-strylphenyl)urea derivatives are potent competitive a-glucosidase inhibitors with very micromolar IC50s [11]
We constructed the homology modeled structure of S. cerevisiae a-glucosidase referenced by published information and used it for the molecular docking study to find out the initial binding mode of compound 12 which is the most active one
Summary
Several glucosidases catalyze the cleavage of glycosidic bonds in oligosaccharides or glycoconjugates and release glucose from the non-reducing end of the oligosaccharide chain. a-glucosidase (EC. 3.2.1.20; a-glucosidase glucohydrolase) is an enzyme that catalyzes the cleavage of glycosidic bond in maltose [1]. From the comparison of initial docked structure and the three representative structures, similar binding mode was observed but average poses mostly different from each other (Figure 5C to 5F) Among these different three local minima, global minimum conformation, the best adjusted conformation for compound 12, was selected by computing and comparing averaged interaction energies (sum of columbic and van der Waals energies) in the last 5 ns of simulation (Table 1). In order to check whether the lowest energy structure is more reasonable for binding of stilbene derivatives than the homology modeled one, negative CDOCKER energies were compared after conducting a several molecular docking simulations of compound 12 with the representative protein conformations (Figure 6). These results suggested that our pharmacophore model is useful for human a-amylase which is the main pharmaceutical target for stibene derivatives
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