Many cancers are associated with abnormal overexpression or activation of AKT, which is concerned with increased cancer cell proliferation and survival . In comparison with normal esophageal mucosa (27.7% or 23/83 cases), high expression levels of the phosphorylated AKT protein were found more (90.4% or 75/83 cases) in patients with esophageal squamous cell carcinoma (ESCC). AKT1 is critical in various physiological activities and these constantly activated activities in multifarious tumors include transcription, apoptosis, glucose mtabolism, cell proliferation, and cell migration. Therefore, the key to inhibit tumor is to find an inhibitor of AKT1.
Recently, the PI3K/AKT signaling pathway is considered to be an potential target in treating cancer . AKT is a central signaling node of the PI3K pathway and could be an ideal target for improving pathway inhibition. At present, a large number of PI3K/AKT pathway inhibitors have been extensively studied. However, the application and clinical significance of those drugs have been largely restricted by such potential adverse effects as pneumonitis and hepatotoxicity [15, 16]. MK-2206, one of allosteric AKT inhibitors, was used for monotherapy treatment. Some study showed the monotherapy treatment of MK-2206 had a good tolerance, however, its impact on patient benefit has been minimal. GSK690693, a potent ATP-competitive AKT inhibitor, has modest kinase selectivity, but its oral is poor . Hence, it is urgent to find more effective inhibitors for clinical applications. In this study, Ipatasertib was chosen as a reference drug.
To do virtual screening and analysis, Discovery Studio’s numerous sections were used in this study. Results indicated that 7764 compounds were eligible to bind stably with AKT1. Based on the LibDock score, further study of the top 20 compounds was pooled.
In order to evaluate the pharmacologic properties of these compounds, ADME and toxicity predictions of the selected compounds were used in this study. Outcomes indicated that ZINC000049872065 and ZINC000021992902 had a good solubility and a good absorption level. Additionally, they were non-inhibitors of CYP2D6 and non-hepatotoxic. Besides, in comparison with other compounds, these two compounds were also found to have less developmental toxicity potential, rodent carcinogenicity and mutagenicity. Hence, ZINC000049872065 and ZINC000021992902 were selected as safe drug candidates and further analysis was performed. For another, the remaining drugs still had a possible function in drug development despite their possessed toxicities or negative effects.
The bonding mechanism and chemical bonds of the selected candidate compounds were also researched. CDOCKER module computation illustrated that ZINC000049872065 and ZINC000021992902 has a lower CDOCKER interaction energy compared with the reference ligand Ipatasertib. The results indicated that Ipatasertib had a lower binding affinity with AKT1 than these two compounds.
In the end, molecular dynamics simulation was used to investigate their stability in the natural environment. Calculation of RMSD and potential energy of these ligand-AKT1 complexes demonstrated the time when the trajectories of each complex reached equilibrium is 15ps. As time goes, RMSD and potential energy of these complexes reached stable state, which showed ZINC000049872065 and ZINC000021992902 could interact with AKT1 and the complexes were stable in the natural environment. On account of the results, these 2 compounds could be used for drug development and refinement.
Screening ideal lead compounds was the most critical step of current drug designation. In this study, a battery of computer-aided virtual techniques was used to identify possible inhibitors of AKT1. LibDock was applied for structure-based screening followed by ADME and toxicity prediction. To confirm the binding affinity mechanism between the ligand and AKT1, molecular docking was conducted. To assess the stability of ligand- AKT1 complexes, molecular dynamics simulations were used. The results indicated that these 2 compounds might potentially influence cancers. But it is all known that without refining and improving some drug thousands of times. Therefore, the refinement and improvement of them are significant in the following research.
Although this study was well-designed and precise measurements have been conducted, some shortcomings still exist. To confirm our results, such further experiments as animal testing will be performed. Besides, more indicators which should be assessed in the future include half-maximal inhibitory concentration and half-maximal effective concentration.