QM/MM–PB/SA scoring of the interaction strength between Akt kinase and apigenin analogues

• The QM/MM–PB/SA is compared with empirical scoring functions and free energy analysis.
• The QM/MM–PB/SA is used to score the binding affinity of apigenin analogues to Akt.
• Kinase assay is performed to solidify the results arising from theoretical analysis.
• Four apigenin analogues are found to exhibit Akt inhibitory activity at nanomolar level.

Identification of small-molecule compounds that can bind specifically and stably to protein targets of biological interest is a challenge task in structure-based drug design. Traditionally, several fast approaches such as empirical scoring functions and free energy analysis have been widely used to fulfill for this purpose. In the current study, we raised the rigorous quantum mechanics/molecular mechanics in combination with semi-empirical Poisson–Boltzmann/surface area (QM/MM–PB/SA) as an efficient strategy to characterize the intermolecular interaction between Akt kinase and its small-molecule ligands, although this hybrid approach is computationally expensive as compared to those empirical methods. In a round of experimental activity reproduction test based on a set of known Akt–inhibitor complexes, QM/MM–PB/SA has been shown to perform much better than two widely used scoring functions as well as the sophisticated MM-PB/SA analysis with or without improvement by molecular dynamics (MD) simulations. Next, the QM/MM–PB/SA was employed to screen for strong Akt binders from an apigenin analogue set. Consequently, four compounds, namely apigenin, quercetin, gallocatechin and myricetin, were suggested to have high binding potency to Akt active site. A further kinase assay was conducted to determine the inhibitory activity of the four promising candidates against Akt kinase, resulting in IC50 values of 38.4, 67.5, 157.1 and 25.5 nM, respectively.

The rigorous QM/MM–PB/SA is employed to screen for strong Akt binders from a set of apigenin analogues and, consequently, four compounds, namely apigenin, quercetin, gallocatechin and myricetin, are suggested to have high binding potency to Akt active site, which are further solidified by a kinase assay.Figure optionsDownload as PowerPoint slide