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Selectivity Mechanism of ATP ‐Competitive Inhibitors for PKB and PKA
Author(s) -
Wu Ke,
Pang Jingzhi,
Song Dong,
Zhu Ying,
Wu Congwen,
Shao Tianqu,
Chen Haifeng
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12472
Subject(s) - chemistry , quantitative structure–activity relationship , protein kinase b , pi3k/akt/mtor pathway , protein kinase a , kinase , homology modeling , in vivo , enzyme , selectivity , in vitro , biochemistry , signal transduction , computational biology , biology , stereochemistry , catalysis , microbiology and biotechnology
Protein kinase B ( PKB ) acts as a central node on the PI 3K 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.