An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted indirubins.
A variation of the bromine substitution from 6- to 7-position converts the glycogen synthase kinase-3alpha/beta-(GSK-3-alpha/beta) selective inhibitor 6-bromoindirubin-3'-oxime (6BIO) to a potent inhibitor of Aurora B and C kinases. The novel indirubin analogue 7-bromoindirubin-3'-oxime (7BIO) demonstrated unexpected selectivity against these two kinases since the homologous kinase Aurora A was poorly inhibited. A hypothesis regarding the 7BIO selectivity profile was stated and validated by docking, molecular dynamics, and free energy perturbation calculations. The residue (Thr217AurA, Glu161AurB, Glu127AurC) located in the active site was identified as a major contributor to the enhanced affinity of 7BIO for Aurora B and C versus Aurora A. Furthermore, the docking events of 7BIO and several of its analogues were approached by quantitative models based on semiempirical scoring functions. In the course of model construction and optimization, a number of important factors influencing the quality of each model like the application of force constraints or the sampling method were determined. Among these factors, the presence and treatment of structurally important water molecules had a pronounced impact on the quality of each model. The final model was validated by use of free energy perturbation calculations.
School of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771, Athens, Greece.
Vassilios
V
Myrianthopoulos
Prokopios
P
Magiatis
Yoan
Y
Ferandin
Alexios-Leandros
AL
Skaltsounis
Laurent
L
Meijer
Emmanuel
E
Mikros
D000595:Amino Acid Sequence; D064127:Aurora Kinases; D001665:Binding Sites; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
C514974:7-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C027185:indirubin