Exploration of the selective binding mechanism of GSK3β via molecular modeling and molecular dynamics simulation studies

Kinase inhibitor selectivity is a major concern for the design of small-molecule compounds. As a member of serine/threonine protein kinase family, glycogen synthase kinase 3β (GSK3β) is involved in diverse biological processes and abnormal dysregulation of its activity has been associated with several pathologies, including type II diabetes, Alzheimer’s disease, bipolar disorders, and cancers. A small-molecule PF-367 significantly inhibited the GSK3 enzymatic activity over its closest cyclin-dependent kinase 2 (CDK2) with >1000-fold selectivity. However, the PF-367 selectively binding to GSK3β over CDK2 has remained unclear. Here, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics_generalized born/surface area (MM_GBSA) binding free energy calculations, as well as the decomposition of binding free energies were performed to investigate the selective binding mechanism of PF-367 to the ATP-binding site of GSK3β over CDK2. The results revealed that the exposure of the terminal triazole ring of PF-367 into the solvent environment may be responsible for the weak binding complex of CDK2−PF-367, which was further confirmed by the binding free energy calculations and the identified key residues (Phe67, Lys85, Thr138, and Arg141) contributing to the binding interaction. The obtained data can not only decipher the origin of selectivity, but also be used for the design of more potent and selective GSK3β inhibitors.