The non-additive contribution of hydroxyl substituents to Akt kinase-apigenin affinity

The natural product apigenin is a flavonoid derivative substituted by three hydroxyl functional groups at positions 4′, 5 and 7 [OH(4′), OH(5) and OH(7)] of the basic flavonoid skeleton, which has shown strong inhibition on the development, proliferation and invasion of tumour cells by binding speci...

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Bibliographic Details
Published in:Molecular simulation 2015-05, Vol.41 (8), p.653-662
Main Authors: Lu, Jian, Zhang, Zhuyi, Ni, Zhong, Shen, Haijun, Tu, Zhigang, Liu, Hanqing, Lu, Rongzhu, Shi, Haifeng
Format: Article
Language:English
Subjects:
Affinity
Akt kinase
apigenin
Binding
binding affinity
Empirical analysis
flavonoid
Flavonoids
Hydroxyl groups
Kinases
Mathematical models
non-additivity
Scoring
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Summary:The natural product apigenin is a flavonoid derivative substituted by three hydroxyl functional groups at positions 4′, 5 and 7 [OH(4′), OH(5) and OH(7)] of the basic flavonoid skeleton, which has shown strong inhibition on the development, proliferation and invasion of tumour cells by binding specifically to Akt kinase to inactivate the Akt signalling pathway. In this study, a typical non-additivity of the three hydroxyl substituents' contributions to Akt-apigenin binding affinity is demonstrated by combination of four empirical scoring functions, molecular dynamics simulations, molecular mechanics-Poisson-Boltzmann/surface area (MM/PBSA) analyses and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. It is found that (i) the empirical scoring functions are incapable of properly reflecting the non-additivity feature, which, however, can be well described by the more rigorous MM/PBSA and QM/MM methods, (ii) the hydroxyl group contributions to ligand binding affinity are deviated significantly from linear additive model due to the strong conjugate effect and σ-effect among them, that is, the co-contribution of the three hydroxyl groups is far less than the sum of their individual contributions and (iii) as might be expected, a strong interactive effect is observed for the two adjacent substituents OH(5) and OH(7) as compared with that of distant OH(5) and OH(4′) as well as OH(7) and OH(4′). In addition, the structural basis, energetic property and molecular mechanism of the non-additivity feature are also explored in detail using the natural population analysis and quantum mechanical calculations.
ISSN:0892-7022
1029-0435
DOI:10.1080/08927022.2014.913099