AKT1是丝氨酸/苏氨酸激酶家族,在调节细胞生长中起关键作用。扩散,新陈代谢,和生存。两大类AKT1抑制剂(变构和ATP竞争性)用于临床开发。两者都可以在特定条件下有效。在这项研究中,我们通过计算方法研究了几种不同抑制剂对AKT1两种构象的影响。我们研究了四种抑制剂的作用,包括MK-2206Miransertib,Herbacetin,还有Shogaol,AKT1蛋白的非活性构象及四种抑制剂的作用,Capivasertib,AT7867,槲皮素,和冬凌草甲素分子对AKT1蛋白活性构象的影响。模拟结果表明,每种抑制剂都能与AKT1蛋白产生稳定的复合物,尽管AKT1/Shogaol和AKT1/AT7867复合物的稳定性低于其他复合物。根据RMSF计算,所述复合物中残基的波动高于其它复合物。与其他两种构象的复合物相比,MK-2206在非活性构象中具有更强的结合自由能亲和力,-203.446kJ/mol。MM-PBSA计算表明,范德华相互作用对AKT1蛋白抑制剂的结合能的贡献大于静电相互作用。
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.