BMC Bioinformatics | |
Exploration of charge states of balanol analogues acting as ATP-competitive inhibitors in kinases | |
Research | |
Muhammad Yusuf1  Ari Hardianto2  Shoba Ranganathan2  Fei Liu2  | |
[1]Department of Chemistry, Universitas Padjadjaran, 45363, Jatinangor, West Java, Indonesia | |
[2]Department of Molecular Sciences, Macquarie University, 2109, Sydney, NSW, Australia | |
关键词: Kinase inhibitors; Ligand charge state; ATP mimic; Molecular modelling; Molecular dynamics simulation; | |
DOI : 10.1186/s12859-017-1955-7 | |
来源: Springer | |
【 摘 要 】
Background(-)-Balanol is an ATP mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is a tumour promoter, PKC isozymes act as tumour promoters or suppressors, depending on the cancer type. In particular, PKCε is frequently implicated in cancer promotion, making it a potential target for anticancer drugs. To improve isozyme selectivity of balanol, exhaustive structural and activity relationship (SAR) studies have been performed in the last two decades, but with limited success. More recently, fluorination on balanol has shown improved selectivity for PKCε, although the fluorine effect is not yet clearly understood. Understanding the origin to this fluorine-based selectivity will be valuable for designing better balanol-based ATP mimicking inhibitors. Computational approaches such as molecular dynamics (MD) simulations can decipher the fluorine effect, provided that correct charges have been assigned to a ligand. Balanol analogues have multiple ionisable functional groups and the effect of fluorine substitutions on the exact charge state of each analogue bound to PKA and to PKCε needs to be thoroughly investigated in order to design highly selective inhibitors for therapeutic applications.ResultsWe explored the charge states of novel fluorinated balanol analogues using MD simulations. For different potential charge states of these analogues, Molecular Mechanics Generalized Born Surface Area (MMGBSA) binding energy values were computed. This study suggests that balanol and the most potent fluorinated analogue (5S fluorine substitution on the azepane ring), have charges on the azepane ring (N1), and the phenolic (C6′′OH) and the carboxylate (C15′′O2H) groups on the benzophenone moiety, when bound to PKCε as well as PKA.ConclusionsTo the best our knowledge, this is the first study showing that the phenolate group is charged in balanol and its analogues binding to the ATP site of PKCε. Correct charge assignments of ligands are important to obtain predicted binding energy values from MD simulations that reflect experimental values. Both fluorination and the local enzymatic environment of the ATP site can influence the exact charge states of balanol analogues. Overall, this study is highly valuable for further rational design of potent balanol analogues selective to PKCε.【 授权许可】
CC BY
© The Author(s). 2017
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO202311097617992ZK.pdf | 1120KB | download | |
12864_2017_3487_Article_IEq15.gif | 1KB | Image | download |
12888_2016_877_Article_IEq9.gif | 1KB | Image | download |
12888_2016_877_Article_IEq10.gif | 1KB | Image | download |
12888_2016_877_Article_IEq11.gif | 1KB | Image | download |
12864_2017_4116_Article_IEq3.gif | 1KB | Image | download |
12864_2017_3487_Article_IEq17.gif | 1KB | Image | download |
12864_2016_2791_Article_IEq1.gif | 1KB | Image | download |
12864_2017_3487_Article_IEq20.gif | 1KB | Image | download |
12864_2016_3353_Article_IEq23.gif | 1KB | Image | download |
12864_2016_3425_Article_IEq1.gif | 1KB | Image | download |
12888_2016_877_Article_IEq18.gif | 1KB | Image | download |
12864_2016_3353_Article_IEq26.gif | 1KB | Image | download |
12864_2016_3074_Article_IEq2.gif | 1KB | Image | download |
12864_2017_4004_Article_IEq23.gif | 1KB | Image | download |
12864_2016_2790_Article_IEq1.gif | 1KB | Image | download |
12864_2017_4132_Article_IEq18.gif | 1KB | Image | download |
12864_2017_3605_Article_IEq1.gif | 1KB | Image | download |
12864_2017_4132_Article_IEq20.gif | 1KB | Image | download |
12864_2017_4132_Article_IEq22.gif | 1KB | Image | download |
12864_2017_3487_Article_IEq34.gif | 1KB | Image | download |
12864_2015_2304_Article_IEq10.gif | 1KB | Image | download |
12864_2017_3670_Article_IEq13.gif | 1KB | Image | download |
12864_2017_3670_Article_IEq14.gif | 1KB | Image | download |
12864_2017_3670_Article_IEq15.gif | 1KB | Image | download |
12864_2017_3990_Article_IEq10.gif | 1KB | Image | download |
12888_2017_1528_Article_IEq1.gif | 1KB | Image | download |
12864_2017_4132_Article_IEq31.gif | 1KB | Image | download |
12864_2017_4133_Article_IEq19.gif | 1KB | Image | download |
12864_2017_4133_Article_IEq20.gif | 1KB | Image | download |
12864_2017_3798_Article_IEq1.gif | 1KB | Image | download |
12864_2017_4359_Article_IEq3.gif | 1KB | Image | download |
【 图 表 】
12864_2017_4359_Article_IEq3.gif
12864_2017_3798_Article_IEq1.gif
12864_2017_4133_Article_IEq20.gif
12864_2017_4133_Article_IEq19.gif
12864_2017_4132_Article_IEq31.gif
12888_2017_1528_Article_IEq1.gif
12864_2017_3990_Article_IEq10.gif
12864_2017_3670_Article_IEq15.gif
12864_2017_3670_Article_IEq14.gif
12864_2017_3670_Article_IEq13.gif
12864_2015_2304_Article_IEq10.gif
12864_2017_3487_Article_IEq34.gif
12864_2017_4132_Article_IEq22.gif
12864_2017_4132_Article_IEq20.gif
12864_2017_3605_Article_IEq1.gif
12864_2017_4132_Article_IEq18.gif
12864_2016_2790_Article_IEq1.gif
12864_2017_4004_Article_IEq23.gif
12864_2016_3074_Article_IEq2.gif
12864_2016_3353_Article_IEq26.gif
12888_2016_877_Article_IEq18.gif
12864_2016_3425_Article_IEq1.gif
12864_2016_3353_Article_IEq23.gif
12864_2017_3487_Article_IEq20.gif
12864_2016_2791_Article_IEq1.gif
12864_2017_3487_Article_IEq17.gif
12864_2017_4116_Article_IEq3.gif
12888_2016_877_Article_IEq11.gif
12888_2016_877_Article_IEq10.gif
12888_2016_877_Article_IEq9.gif
12864_2017_3487_Article_IEq15.gif
【 参考文献 】
- [1]
- [2]
- [3]
- [4]
- [5]
- [6]
- [7]
- [8]
- [9]
- [10]
- [11]
- [12]
- [13]
- [14]
- [15]
- [16]
- [17]
- [18]
- [19]
- [20]
- [21]
- [22]
- [23]
- [24]
- [25]
- [26]
- [27]
- [28]
- [29]
- [30]
- [31]
- [32]
- [33]
- [34]
- [35]
- [36]
- [37]
- [38]
- [39]
- [40]
- [41]
- [42]
- [43]
- [44]
- [45]
- [46]
- [47]
- [48]
- [49]
- [50]