title: Structural basis of valmerins as dual inhibitors of GSK3β/CDK5.
abstract: 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 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3β/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 GSK3β/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3β/CDK5 and the valmerin-19 bound to GSK3β/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3β/CDK5 inhibitors.
authors.affiliation: Depatment of Spinal Surgery, Affiliated Hospital of Weifang Medical University, Weifang, 261000, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Li
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Zibin
authors.initials: Z
authors.lastname: Tian
authors.forename: Houling
authors.initials: H
authors.lastname: Zhao
authors.forename: Da
authors.initials: D
authors.lastname: Liang
authors.forename: Weisong
authors.initials: W
authors.lastname: Li
authors.forename: Yujin
authors.initials: Y
authors.lastname: Qiu
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Lu
mesh_terms: D001665:Binding Sites; D016000:Cluster Analysis; D017076:Computer-Aided Design; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D004735:Energy Transfer; D004795:Enzyme Stability; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D054836:Indolizidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D054836:Indolizidines; D008024:Ligands; D047428:Protein Kinase Inhibitors; C000602447:valmerin-19; D014508:Urea; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3