Molecular insights into the behavior of the allosteric and ATP-competitive inhibitors in interaction with AKT1 protein: A molecular dynamics study

by Selleckchem | Jul 12 2023

AKT1 is a family of serine/threonine kinases that play a key role in regulating cell growth, proliferation, metabolism, and survival. Two significant classes of AKT1 inhibitors (allosteric and ATP-competitive) are used in clinical development, and both of them could be effective in specific conditions. In this study, we investigated the effect of several different inhibitors on two conformations of the AKT1 by computational approach. We studied the effects of four inhibitors, including MK-2206, Miransertib, Herbacetin, and Shogaol, on the inactive conformation of AKT1 protein and the effects of four inhibitors, Capivasertib, AT7867, Quercetin, and Oridonin molecules on the active conformation of AKT1 protein. The results of simulations showed that each inhibitor creates a stable complex with AKT1 protein, although AKT1/Shogaol and AKT1/AT7867 complexes showed less stability than other complexes. Based on RMSF calculations, the fluctuation of residues in the mentioned complexes is higher than in other complexes. As compared to other complexes in either of its two conformations, MK-2206 has a stronger binding free energy affinity in the inactive conformation, -203.446 kJ/mol. MM-PBSA calculations showed that the van der Waals interactions contribute more than the electrostatic interactions to the binding energy of inhibitors to AKT1 protein.

Comments:

The study you described investigated the effects of different AKT1 inhibitors on two conformations of the AKT1 protein using a computational approach. AKT1 is a family of serine/threonine kinases that have important roles in various cellular processes. The two classes of AKT1 inhibitors studied were allosteric inhibitors and ATP-competitive inhibitors.

The study examined the effects of four inhibitors on the inactive conformation of AKT1 protein: MK-2206, Miransertib, Herbacetin, and Shogaol. Additionally, the effects of four inhibitors on the active conformation of AKT1 protein were investigated: Capivasertib, AT7867, Quercetin, and Oridonin.

The simulations revealed that each inhibitor formed a stable complex with the AKT1 protein. However, the AKT1/Shogaol and AKT1/AT7867 complexes exhibited lower stability compared to the other complexes. The fluctuation of residues in these two complexes was higher than in the other complexes, as determined by root-mean-square fluctuation (RMSF) calculations.

Regarding the binding free energy affinity, MK-2206 demonstrated the strongest binding affinity in the inactive conformation, with a value of -203.446 kJ/mol. This indicates a high affinity of MK-2206 for the inactive form of AKT1.

The study also utilized MM-PBSA calculations to determine the contributions of different interactions to the binding energy of inhibitors to the AKT1 protein. The results showed that van der Waals interactions contributed more to the binding energy than electrostatic interactions in the studied inhibitor-AKT1 complexes.

Overall, this computational study provides insights into the effects of different AKT1 inhibitors on the protein's conformations and sheds light on their binding mechanisms and binding energy contributions.