Selectivity Mechanism of ATP-Competitive Inhibitors for PKB and PKA.
Protein kinase B (PKB) acts as a central node on the PI3K kinase pathway. Constitutive activation and overexpression of PKB have been identified to involve in various cancers. However, protein kinase A (PKA) sharing high homology with PKB is essential for metabolic regulation. Therefore, specific targeting on PKB is crucial strategy in drug design and development for antitumor. Here, we had revealed the selectivity mechanism for PKB inhibitors with molecular dynamics simulation and 3D-QSAR methods. Selective inhibitors of PKB could form more hydrogen bonds and hydrophobic contacts with PKB than those with PKA. This could explain that selective inhibitor M128 is more potent to PKB than to PKA. Then, 3D-QSAR models were constructed for these selective inhibitors and evaluated by test set compounds. 3D-QSAR model comparison of PKB inhibitors and PKA inhibitors reveals possible methods to improve the selectivity of inhibitors. These models can be used to design new chemical entities and make quantitative prediction of the specific selective inhibitors before resorting to in vitro and in vivo experiment.
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Ke
K
Wu
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Jingzhi
J
Pang
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Dong
D
Song
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Ying
Y
Zhu
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Congwen
C
Wu
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Tianqu
T
Shao
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.|Shanghai Center for Bioinformation Technology, 1275 Keyuan Road, Shanghai, 200235, China.
Haifeng
H
Chen
D000255:Adenosine Triphosphate / Q000737:chemistry*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D062126:Databases, Chemical; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases
3D-QSAR; molecular dynamics simulation; protein kinase A; protein kinase B; selectivity