Binding mode analyses and pharmacophore model development for stilbene derivatives as a novel and competitive class of α-glucosidase inhibitors
MetadataShow full item record
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.
This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by/4.0/
Showing items related by title, author, creator and subject.
Gandhi, Neha Sureshchandra (2011)Glycosaminoglycans (GAGs) are ubiquitous complex carbohydrate molecules present on the cell surfaces and in extracellular matrices (ECM) of vertebrate and invertebrate tissues. The interactions of sulphated GAGs such as ...
Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor DesignArooj, Mahreen; Kim, Songmi; Sakkiah, Sugunadevi; Ping Cao, Guang; Lee, Yuno; Woo Lee, Keun (2013)Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with ...
Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and InhibitionArooj, Mahreen; Thangapandian, S.; John, S.; Hwang, S.; Park, J.; Lee, K. (2012)To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. ...