The use of docking-based comparative intermolecular contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators

• Published in: Journal of computer-aided molecular design Vol. 28; no. 5; pp. 509 - 547
• Main Authors: Taha, Mutasem O., Habash, Maha, Khanfar, Mohammad A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2014; Springer Nature B.V
• Subjects: Algorithms; Animal Anatomy; Binding sites; CAD; Chemistry; Chemistry and Materials Science; Computer aided design; Computer Applications in Chemistry; Design engineering; Docking; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; Enzymes; Glucokinase - chemistry; Glucokinase - metabolism; Histology; Hyperglycemia; Molecular Docking Simulation; Molecular structure; Morphology; Optimization; Pharmaceutical sciences; Physical Chemistry; Quantitative Structure-Activity Relationship; Searching; Shortages; Three dimensional; Docking; In-silico screening; In vitro testing; dbCICA; LigandFit; Glucokinase enzyme
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-014-9740-4

Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of docking validation methods prompted us to use our new 3D-QSAR analysis, namely, docking-based comparative intermolecular contacts analysis (dbCICA), to validate docking configurations performed on a group of GKAs within GK binding site. dbCICA assesses the consistency of docking by assessing the correlation between ligands’ affinities and their contacts with binding site spots. Optimal dbCICA models were validated by receiver operating characteristic curve analysis and comparative molecular field analysis. dbCICA models were also converted into valid pharmacophores that were used as search queries to mine 3D structural databases for new GKAs. The search yielded several potent bioactivators that experimentally increased GK bioactivity up to 7.5-folds at 10 μM.