Virtual Screening of Natural Compounds as Potential PI3K-AKT1 Signaling Pathway Inhibitors and Experimental Validation

Dotolo, Serena; Cervellera, Carmen; Russo, Maria; Russo, Gian Luigi; Facchiano, Angelo

doi:10.3390/molecules26020492

Cited by 19 publications

(24 citation statements)

References 50 publications

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Section: Resultssupporting

confidence: 55%

“…Moreover, our molecular docking study showed that, among the four identified targets, AKT1 showed the highest binding affinity for curcumin, indicating that AKT1 is the most potent target. The calculated binding energy of curcumin to AKT1 was reasonably low as <−9.0 Kcal/mol, indicating a possible inhibitory effect [ 15 ]. Lastly, our in vitro study demonstrated that curcumin was effective against influenza virus in both pre- and post-treatment paradigms, and confirmed inhibition of mRNA level of AKT expression suggesting that curcumin could be useful as either a prophylactic or therapeutic influenza agent.…”

Section: Discussionmentioning

confidence: 99%

“…In AKT1, the docking result of the two forms of curcumin was compared to that of the original ligand, AKT1 inhibitor (IQO), in the selected AKT1 structure (PDB ID: 3O96) (Table 3) [10]. The AKT1 inhibitor shows a very low binding energy of <−14.0 Kcal/mol and curcumin also shows reasonable binding energy of <−9.0 Kcal/mol, compared to the previously published docking study [15]. In AKT1, the docking result of the two forms of curcumin was compared to that of the original ligand, AKT1 inhibitor (IQO), in the selected AKT1 structure (PDB ID: 3O96) (Table 3) [10].…”

Section: Molecular Docking Analysismentioning

confidence: 99%

“…In AKT1, the docking result of the two forms of curcumin was compared to that of the original ligand, AKT1 inhibitor (IQO), in the selected AKT1 structure (PDB ID: 3O96) (Table 3) [10]. The AKT1 inhibitor shows a very low binding energy of <−14.0 Kcal/mol and curcumin also shows reasonable binding energy of <−9.0 Kcal/mol, compared to the previously published docking study [15]. To measure the anti-influenza actions of curcumin in MDCK cells, we assessed its effect on the virus cycle by performing antiviral experiments using three paradigms: pretreatment, co-treatment, and post-treatment.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

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Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches

et al. 2021

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The influenza virus is a constantly evolving pathogen that challenges medical and public health systems. Traditionally, curcumin has been used to treat airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate common targets of curcumin and influenza infection and underlying mechanisms, we employed network pharmacology and molecular docking approaches and confirmed results using in vitro experiments. Biological targets of curcumin and influenza were collected, and potential targets were identified by constructing compound–disease target (C-D) and protein–protein interaction (PPI) networks. The ligand–target interaction was determined using the molecular docking method, and in vitro antiviral experiments and target confirmation were conducted to evaluate curcumin’s effects on influenza. Our network and pathway analyses implicated the four targets of AKT1, RELA, MAPK1, and TP53 that could be involved in the inhibitory effects of curcumin on influenza. The binding energy calculations of each ligand–target interaction in the molecular docking showed that curcumin bound to AKT1 with the highest affinity among the four targets. In vitro experiments, in which influenza virus-infected MDCK cells were pre-, co-, or post-treated with curcumin, confirmed curcumin’s prophylactic and therapeutic effects. Influenza virus induction increased the level of mRNA expression of AKT in MDCK cells, and the level was attenuated by curcumin treatment. Collectively, our findings identified potential targets of curcumin against influenza and suggest curcumin as a potential therapy for influenza infection.

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Section: Resultssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Docking Analysismentioning

confidence: 99%

“…In AKT1, the docking result of the two forms of curcumin was compared to that of the original ligand, AKT1 inhibitor (IQO), in the selected AKT1 structure (PDB ID: 3O96) (Table 3) [10]. The AKT1 inhibitor shows a very low binding energy of <−14.0 Kcal/mol and curcumin also shows reasonable binding energy of <−9.0 Kcal/mol, compared to the previously published docking study [15]. To measure the anti-influenza actions of curcumin in MDCK cells, we assessed its effect on the virus cycle by performing antiviral experiments using three paradigms: pretreatment, co-treatment, and post-treatment.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

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Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches

et al. 2021

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“…In this scenario, we recently completed a computational screening to search for compounds that are able to bind the AKT protein by generating a pharmacophore model based on the experimental structure of AKT-1 in complex with IQO, a well-known AKT-1 inhibitor. We selected two compounds, ZINC2429155 (STL1) ( Figure 1 b) and ZINC1447881 (AC1) both suitable in silico to bind AKT-1 in an allosteric site, but only one, STL1, was able in vitro to reduce Ser473 phosphorylation, thus inhibiting the PI 3 K/AKT pathway [ 7 ]. However, the inactivation of AKT phosphorylation by STL1 was not sufficient to induce cell death in the malignant cell line investigated as represented by the HG-3 cells, a lymphoblastoid cell line with B1 cell characteristics established from a CLL clone by the in vitro EBV infection [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

STL1, a New AKT Inhibitor, Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line

et al. 2021

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Using a pharmacophore model based on the experimental structure of AKT-1, we recently identified the compound STL1 (ZINC2429155) as an allosteric inhibitor of AKT-1. STL1, was able to reduce Ser473 phosphorylation, thus inhibiting the PI3K/AKT pathway. Moreover, we demonstrated that the flavonoid quercetin downregulated the phosphorylated and active form of AKT. However, in this case, quercetin inhibited the PI3K/AKT pathway by directly binding the kinases CK2 and PI3K. In the present work, we investigated the antiproliferative effects of the co-treatment quercetin plus STL1 in HG-3 cells, derived from a patient affected by chronic lymphocytic leukemia. Quercetin and STL1 in the mono-treatment maintained the capacity to inhibit AKT phosphorylation on Ser473, but did not significantly reduce cell viability. On the contrary, they activated a protective form of autophagy. When the HG-3 cells were co-treated with quercetin and STL1, their association synergistically (combination index < 1) inhibited cell growth and induced apoptosis. The combined treatment caused the switch from protective to non-protective autophagy. This work demonstrated that cytotoxicity could be enhanced in a drug-resistant cell line by combining the effects of different inhibitors acting in concert on PI3K and AKT kinases.

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Synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and its glycoside from quinoa

Zhang,

Zhao,

et al. 2024

Biotech and App Biochem

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Although a series of studies confirm the bioactivities of hederagenin and its glycosides, their synergistic effects and potential mechanisms are still worthy of further exploration. This work investigated the synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and hederagenin 28‐O‐β‐d‐glucopyranoside (28‐Glc‐hederagenin). Hederagenin and 28‐Glc‐hederagenin inhibited HeLa cell growth and their combination further strengthened this effect. The combination of hederagenin and 28‐Glc‐hederagenin significantly increased the rate of apoptotic cells, suggesting the presence of a synergistic effect between the two substances. This combination also enhanced in vitro antioxidant activity compared with individual treatments. A network pharmacology and molecular docking‐based approach was performed to explore the underlying mechanisms of hederagenin and 28‐Glc‐hederagenin against cervical cancer and oxidant damage. This work identified 18 related Kyoto Encyclopedia of Genes and Genome pathways, 202 related biological process terms, 17 related CC terms, and 35 related molecular function terms and then revealed 30 nodes and 196 edges. Subsequently, two highly connected clusters and the top four targets were identified. Molecular docking showed potent binding affinity of hederagenin and 28‐Glc‐hederagenin toward core targets associated with both cervical cancer and oxidant damage. This work may provide scientific basis for the combined use of hederagenin and its glycosides as dietary supplements.

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Virtual Screening of Natural Compounds as Potential PI3K-AKT1 Signaling Pathway Inhibitors and Experimental Validation

Cited by 19 publications

References 50 publications

Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches

Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches

STL1, a New AKT Inhibitor, Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line

Synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and its glycoside from quinoa

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