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Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Modeling, docking and molecular dynamics (MD) simulations of BL-AD008 targeting AMPK and ZIPK
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Figure 4: Modeling, docking and molecular dynamics (MD) simulations of BL-AD008 targeting AMPK and ZIPK

Mentions: Molecular docking calculations were first performed for BL-AD008 without explicit active site water molecules. The ligand structures with the most favorable binding free energies and reasonable orientations were selected as the optimal docked conformations. 5ns MD simulations were successfully performed on AMPK–BL-AD008 and ZIPK-BL-AD008 complexes (Figure 4A). To gauge whether the MD simulations were stable and whether they converged, energetic and structural properties were monitored during the course of MD simulation. The low root-mean-square deviation (RMSD) fluctuations and the convergence of the energies, temperatures, and pressures of the systems observed indicated well-behaved systems. The RMSDs between the complexes and ligand structures obtained during the trajectories and the initial structures were shown (Figure 4B). The averaged RMSD during the last 3 ns for AMPK–BL-AD008 and ZIPK-BL-AD008 are 0.18 and 0.16 nm, respectively, suggesting the overall stable structures after approximately 3 ns simulation. In this study, we showed that compound A1 could bind to AMPK stably. The benzene ring of compound form interaction with residue LYS-31, and also form hydrophobic interaction with VAL-11, LEU-18, PHE-90 and ILE-46. For compound BL-AD008, there are two hydrogen bonds formed by residue ASN-48 and LYS-31., Cl atom of BL-AD008 could form interaction with PHE-90. BL-AD008 can form hydrophobic interaction with residue VAL-11, LEU-18, PHE-90, ILE-46 and VAL-24. Thus, the binding energy of BL-AD008 is much lower than A1 (Figure 4).


Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

Modeling, docking and molecular dynamics (MD) simulations of BL-AD008 targeting AMPK and ZIPK
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480736&req=5

Figure 4: Modeling, docking and molecular dynamics (MD) simulations of BL-AD008 targeting AMPK and ZIPK
Mentions: Molecular docking calculations were first performed for BL-AD008 without explicit active site water molecules. The ligand structures with the most favorable binding free energies and reasonable orientations were selected as the optimal docked conformations. 5ns MD simulations were successfully performed on AMPK–BL-AD008 and ZIPK-BL-AD008 complexes (Figure 4A). To gauge whether the MD simulations were stable and whether they converged, energetic and structural properties were monitored during the course of MD simulation. The low root-mean-square deviation (RMSD) fluctuations and the convergence of the energies, temperatures, and pressures of the systems observed indicated well-behaved systems. The RMSDs between the complexes and ligand structures obtained during the trajectories and the initial structures were shown (Figure 4B). The averaged RMSD during the last 3 ns for AMPK–BL-AD008 and ZIPK-BL-AD008 are 0.18 and 0.16 nm, respectively, suggesting the overall stable structures after approximately 3 ns simulation. In this study, we showed that compound A1 could bind to AMPK stably. The benzene ring of compound form interaction with residue LYS-31, and also form hydrophobic interaction with VAL-11, LEU-18, PHE-90 and ILE-46. For compound BL-AD008, there are two hydrogen bonds formed by residue ASN-48 and LYS-31., Cl atom of BL-AD008 could form interaction with PHE-90. BL-AD008 can form hydrophobic interaction with residue VAL-11, LEU-18, PHE-90, ILE-46 and VAL-24. Thus, the binding energy of BL-AD008 is much lower than A1 (Figure 4).

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus