Abstract
The serine/threonine Akt kinase signaling pathway plays an essential role not only in tumorigenesis but also in the potential response to anticancer therapeutic agents. Therefore, aiming to identify potent and selective Akt inhibitors, a novel series of benzimidazole derivatives were designed and docked within the crystal structure of Akt1 kinase. In order to predict their selectivity, the hit compounds were docked against the protein kinase A (PKA), which is the closely related AGC family kinase protein. Moreover, in-silico ADMET-related descriptors were estimated to predict the pharmacokinetic properties for the selected compounds. Among the designed molecules, four compounds were found to have the best binding affinity and good selectivity to Akt1 kinase, furthermore, those compounds had acceptable ADMET properties and were predicted to be non-mutagenic, which could account them as promising Akt1 inhibitory agents for further investigations.
Highlights
Akt (Protein kinase B (PKB)) is a serine/threonine protein kinase that belongs to the AGC family group of kinases [1]
Akt family presents as three isoforms: Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ, all of which consist of three conserved structural features: an N-terminal Pleckstrin homology (PH) domain, an ATP binding central kinase domain, and a C-terminal hydrophobic motif (HM)
Based on the abovementioned facts, we describe the application of structure-based drug design (SBDD) techniques for the rapid discovery of new potent and selective series of benzimidazole-derived ATP-competitive inhibitors of Akt kinase
Summary
Akt (Protein kinase B (PKB)) is a serine/threonine protein kinase that belongs to the AGC family group of kinases [1]. Akt is a key mediator of the PI3K/Akt pathway that regulates a number of cellular processes including cell survival, growth, proliferation, and angiogenesis in response to many different external stimuli such as growth factors and cytokines. This wide range of effects is caused by Akt-mediated phosphorylation of numerous downstream substrates such as BAD, FOXO transcription factors, TSC2, P21Waf1/Cip, P27Kip, and eNOS [4] [5]. Overexpression or activating mutations of upstream growth factor receptors such as EGFR and PDGFR lead to Akt activation, as do point mutations of PIK3CA, the gene encodes the catalytic p110α subunit of PI3K, that occur in breast, colon, and endometrial cancers [5]. Akt gene itself can be amplified in several lines of cancer [8], and the transforming mutation Akt1E17K, which results in constitutively active enzyme [9] [10], has been found in breast, bladder, cervix, and prostate cancers [8]
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