Mechanism of zinc ejection by disulfiram in nonstructural protein 5A

Rehman, Ashfaq Ur; Zhen, Guodong; Zhong, Bozitao; Ni, Duan; Li, Jiayi; Nasır, Abdul; Gabr, Moustafa T.; Rafiq, Humaira; Wadood, Abdul; Lu, Shaoyong; Zhang, Jian; Chen, Haifeng

doi:10.1039/d0cp06360f

Cited by 29 publications

(11 citation statements)

References 71 publications

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“…Each system was placed into a cubic box of TIP3P water molecules, and a water layer with a thickness of 12 Å was covered around the c-Myc-G4/ligand complex (Rehman et al, 2021). To make it electrically neutral, an appropriate amount of K + was added to each system to replace the same number of water molecules.…”

Section: Simulation and Mm/gbsa Free Energy Calculationmentioning

confidence: 99%

Structure‐based discovery of Licoflavone B and Ginkgetin targeting c‐Myc G‐quadruplex to suppress c‐Myc transcription and myeloma growth

et al. 2022

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G‐quadruplex (G4), present in the c‐Myc promoter, has emerged as an attractive cancer‐specific molecular target for drug development. So, the discovery of small molecules to stabilize c‐Myc‐G4 to inhibit transcription of c‐Myc protein is of great significance. Herein, a combined molecular docking‐based virtual screening strategy, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing L6000 Natural Compound Library. Four natural compounds, including Licoflavone B, Demethyleneberberine, Ginkgetin, and Mulberroside C, were predicted to have preferable binding affinities to c‐Myc G4 and then selected for commercial purchase and experimental evaluation. Compounds Licoflavone B and Ginkgetin can significantly inhibit myeloma cell proliferation, with IC50 values <8 μM against the RPMI‐8226 cell line. Moreover, our data demonstrated that the two compounds could simultaneously downregulate c‐Myc transcription and expression. Collectively, compounds Licoflavone B and Ginkgetin might be regarded as new candidates for the development of the more potent c‐Myc‐G4 stabilizers in the future.

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Section: Simulation and Mm/gbsa Free Energy Calculationmentioning

confidence: 99%

Structure‐based discovery of Licoflavone B and Ginkgetin targeting c‐Myc G‐quadruplex to suppress c‐Myc transcription and myeloma growth

et al. 2022

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“…In order to unravel the predominant collective motions of different STK17B states and capture their essential degrees of freedom, we conducted principal component analysis (PCA) of STK17B in the apo, ADP-bound, and ligand-bound states. Based on the PCA, the first two principal modes of motion (i.e., principal components 1 and 2, PC1 and PC2) provide information regarding to the large-amplitude motions of different STK17B states, which represent their functional dynamics ( Masterson et al, 2011 ; Chen et al, 2019 ; Chen et al, 2021 ; He et al, 2021 ; Okeke et al, 2021 ; Rehman et al, 2021 ). In PCA, we selected all simulated trajectories for each system and subjected to RMS-fit to the same initial structure to rule out the translational and rotational motions of the protein.…”

Section: Resultsmentioning

confidence: 99%

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Liu

et al. 2022

Front. Mol. Biosci.

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As a member of the death-associated protein kinase family of serine/threonine kinases, the STK17B has been associated with diverse diseases such as hepatocellular carcinoma. However, the conformational dynamics of the phosphate-binding loop (P-loop) in the determination of inhibitor selectivity profile to the STK17B are less understood. Here, a multi-microsecond length molecular dynamics (MD) simulation of STK17B in the three different states (ligand-free, ADP-bound, and ligand-bound states) was carried out to uncover the conformational plasticity of the P-loop. Together with the analyses of principal component analysis, cross-correlation and generalized correlation motions, secondary structural analysis, and community network analysis, the conformational dynamics of the P-loop in the different states were revealed, in which the P-loop flipped into the ADP-binding site upon the inhibitor binding and interacted with the inhibitor and the C-lobe, strengthened the communication between the N- and C-lobes. These resulting interactions contributed to inhibitor selectivity profile to the STK17B. Our results may advance our understanding of kinase inhibitor selectivity and offer possible implications for the design of highly selective inhibitors for other protein kinases.

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“…Principal component analysis (PCA) is a useful method to show slow motion dynamics of proteins, named essential dynamics ( Rehman et al, 2019 ; Neves Cruz et al, 2020 ; Rehman et al,2021 ). According to PCA, the covariance matrix of Cα atoms was diagonalized to generate a set of eigenvalues and the corresponding eigenvectors.…”

Section: Methodsmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

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Mechanism of zinc ejection by disulfiram in nonstructural protein 5A

Abstract: Hepatitis C virus (HCV) is a notorious member of the enveloped, positive-strand RNA flavivirus family. Non-structural protein 5A (NS5A) plays a key role in HCV replication and assembly. NS5A is...

Cited by 29 publications

References 71 publications

Structure‐based discovery of Licoflavone B and Ginkgetin targeting c‐Myc G‐quadruplex to suppress c‐Myc transcription and myeloma growth

Structure‐based discovery of Licoflavone B and Ginkgetin targeting c‐Myc G‐quadruplex to suppress c‐Myc transcription and myeloma growth

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

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