Novel glucokinase activators: A structure-based pharmacophore modeling, QSAR analysis, and molecular dynamics approach

Glucokinase (GK) activators are promising candidates for type 2 diabetes treatment. This study utilized structure-based pharmacophore modeling and QSAR analysis to identify novel activators. Virtual screening of a 250,000-compound library yielded eight new candidates with significant in vitro activity (over 50% activation at 25 µg/mL) and diverse structures. Molecular dynamics simulations revealed a potential mechanism involving a transient loop flip in the GK allosteric site, aligning with known activator behavior. The leading candidate, NSC12516, displayed superior hydrogen bonding with key residues (compared to known activator MRK501) and potentially stronger binding affinity due to favorable energetics. These findings clear the way for developing potent and selective GK activators for type 2 diabetes.