Structural basis of valmerins as dual inhibitors of GSK3β/CDK5

Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3 beta (GSK3 beta) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3 beta/CDK5 were calculated to be -12.60 +/- 2.28 kcal mol(-1) and -11.85 +/- 2.54 kcal mol(-1), respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3 beta/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3 beta/CDK5 and the valmerin-19 bound to GSK3 beta/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3 beta/CDK5 inhibitors.