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
详细信息 查看全文
- 作者：Vassilios Myrianthopoulos ; Prokopios Magiatis ; Yoan Ferandin ; Alexios-Leandros Skaltsounis ; Laurent Meijer ; Emmanuel Mikros
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 23, 2007
- 年：2007
- 卷：50
- 期：17
- 页码：4027 - 4037
- 全文大小：432K
- 年卷期：v.50,no.17(August 23, 2007)
- ISSN：1520-4804
文摘
A variation of the bromine substitution from 6- to 7-position converts the glycogen synthase kinase-3
/
-(GSK-3-/) selective inhibitor 6-bromoindirubin-3'-oxime (6BIO) to a potent inhibitor of Aurora B and Ckinases. The novel indirubin analogue 7-bromoindirubin-3'-oxime (7BIO) demonstrated unexpected selectivityagainst these two kinases since the homologous kinase Aurora A was poorly inhibited. A hypothesis regardingthe 7BIO selectivity profile was stated and validated by docking, molecular dynamics, and free energyperturbation calculations. The residue (Thr217AurA, Glu161AurB, Glu127AurC) located in the active site wasidentified 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 quantitativemodels based on semiempirical scoring functions. In the course of model construction and optimization, anumber of important factors influencing the quality of each model like the application of force constraintsor the sampling method were determined. Among these factors, the presence and treatment of structurallyimportant water molecules had a pronounced impact on the quality of each model. The final model wasvalidated by use of free energy perturbation calculations.
/-(GSK-3-/) selective inhibitor 6-bromoindirubin-3'-oxime (6BIO) to a potent inhibitor of Aurora B and Ckinases. The novel indirubin analogue 7-bromoindirubin-3'-oxime (7BIO) demonstrated unexpected selectivityagainst these two kinases since the homologous kinase Aurora A was poorly inhibited. A hypothesis regardingthe 7BIO selectivity profile was stated and validated by docking, molecular dynamics, and free energyperturbation calculations. The residue (Thr217AurA, Glu161AurB, Glu127AurC) located in the active site wasidentified 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 quantitativemodels based on semiempirical scoring functions. In the course of model construction and optimization, anumber of important factors influencing the quality of each model like the application of force constraintsor the sampling method were determined. Among these factors, the presence and treatment of structurallyimportant water molecules had a pronounced impact on the quality of each model. The final model wasvalidated by use of free energy perturbation calculations.