In silico toxicity evaluation of Salubrinal and its analogues

Zadorozhnii, Pavlo V.; Kiselev, V. V.; Харченко, А. В.

doi:10.1016/j.ejps.2020.105538

Cited by 17 publications

(10 citation statements)

References 138 publications

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“…In particular, as pointed out in a recent co-authored paper, an in-depth visual inspection reveals the presence of an atypical BS conformation in 5 VA 1 (Figure S1 in the Supporting Information). Based on that, 5 VA 1 has been widely employed as the structure of choice to perform molecular docking simulations. ,− However, such a structural model suffers from two important limitations, which are as follows: (i) it has a resolution (3.7 Å), which is too low to provide an atomic model of the protein and (ii) the model was derived in the absence of a ligand, thus totally neglecting the BS conformational rearrangement occurring upon ligand binding (i.e., induced-fit effects).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, based on a comparative analysis of all of the derived classifiers, we concluded that the integration of docking scores and molecular interaction fingerprints is a winning strategy to maximize model performance, as the proposed method outperforms that based on docking scores only. Importantly, much more reliable docking-based predictions are obtained using a new protein conformation returned by IFD simulations (made available in the Supporting Information as a. pdb file) instead of the cryo-EM model, as it is (i.e., PDB code: 5VA1), which is the usual practice. ,− From a methodological point of view, the study represents the first attempt to incorporate the information provided by docking poses in structure-based classifiers using a LASSO SVM regularized strategy thus providing a new computational workflow to be used in the context of predictive toxicology.…”

Section: Discussionmentioning

confidence: 99%

“…It is worth noting that most of these structure-based investigations were performed employing homology models based on the crystal structure of other K + channels, − as the first near-atomic resolution structure of hERG was determined only recently through single-particle cryoelectron microscopy. In particular, among the different models deposited by the authors, the one provided with the best resolution (3.7 Å PDB code: 5VA1) is today emerging as the structure of choice to perform molecular docking simulations, as highlighted by the recent literature. ,− Despite providing insights into the molecular determinants of drug binding, all of these studies focus on small data sets of compounds already proved to be (or potentially be) hERG binders. In other words, they do not provide any useful model for discerning hERG binders from safe compounds.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Creanza

Delre

Ancona

et al. 2021

J. Chem. Inf. Model.

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Drug-induced blockade of the human ether-a-go-gorelated gene (hERG) channel is today considered the main cause of cardiotoxicity in postmarketing surveillance. Hence, several ligandbased approaches were developed in the last years and are currently employed in the early stages of a drug discovery process for in silico cardiac safety assessment of drug candidates. Herein, we present the first structure-based classifiers able to discern hERG binders from nonbinders. LASSO regularized support vector machines were applied to integrate docking scores and protein−ligand interaction fingerprints. A total of 396 models were trained and validated based on: (i) high-quality experimental bioactivity information returned by 8337 curated compounds extracted from ChEMBL (version 25) and (ii) structural predictor data. Molecular docking simulations were performed using GLIDE and GOLD software programs and four different hERG structural models, namely, the recently published structures obtained by cryoelectron microscopy (PDB codes: 5VA1 and 7CN1) and two published homology models selected for comparison. Interestingly, some classifiers return performances comparable to ligand-based models in terms of area under the ROC curve (AUC MAX = 0.86 ± 0.01) and negative predictive values (NPV MAX = 0.81 ± 0.01), thus putting forward the herein proposed computational workflow as a valuable tool for predicting hERG-related cardiotoxicity without the limitations of ligand-based models, typically affected by low interpretability and a limited applicability domain. From a methodological point of view, our study represents the first example of a successful integration of docking scores and protein−ligand interaction fingerprints (IFs) through a support vector machine (SVM) LASSO regularized strategy. Finally, the study highlights the importance of using hERG structural models accounting for ligand-induced fit effects and allowed us to select the best-performing protein conformation (made available in the Supporting Information, SI) to be employed for a reliable structure-based prediction of hERG-related cardiotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Creanza

Delre

Ancona

et al. 2021

J. Chem. Inf. Model.

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show abstract

“…Sal had no significant effect on ACC cells at low does (<75 μm) (Figure S1). e major reason is supposed to be that the concentration of Sal action in different organ cells is different [30].…”

Section: Discussionmentioning

confidence: 99%

Salubrinal Regulates the Apoptosis of Adrenocortical Carcinoma Cells via the PERK/eIF2α/ATF4 Signaling Pathway

Liang

Huang

et al. 2021

International Journal of Endocrinology

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The protein-kinase-R- (PKR-) like endoplasmic reticulum kinase (PERK) signaling pathway is a well-known promoter of cell apoptosis. In this study, we aimed to determine whether salubrinal (Sal), a selective activator of eukaryotic translation initiation factor 2 (eIF2α), can induce apoptosis of human adrenocortical carcinoma (ACC) cell via activating the PERK/eIF2α/ATF4 signaling pathway, and the potential mechanisms of this action were explored. The ACC cell lines, including SW-13 and NCI–H295 R, were used. 3-(4,5)-Dimethylthiazol(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, cell scratch experiments, flow cytometry, and JC-1 staining assays were performed to detect the cell viability, cell migration, and cell apoptosis. The expression of PERK/eIF2α/ATF4 signaling-pathway-related proteins and apoptosis-related proteins was detected by western blot (WB). Intracellular Ca2+ ion concentration was determined by a confocal laser scanning microscope. The results showed that Sal inhibited the migration and proliferation of ACC cells. Sal remarkably increased the influx of Ca2+ ion and the apoptosis rate of ACC cells in vitro. Furthermore, the expression levels of PERK/eIF2α/ATF4 signaling-related proteins and apoptosis-related proteins were upregulated in the treatment of Sal. The research demonstrated that Sal reduces the cell viability, increases the intracellular calcium concentration, and promotes the apoptosis of ACC cells in vitro through increasing the phosphorylation level of eIF2α and activating the PERK/eIF2α/ATF4 signaling. PERK/eIF2α/ATF4 is expected to act as a potential therapeutic target for the treatment of adrenocortical carcinoma.

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“…Homologous modeling, assisted by other analysis tools, such as molecular docking, is used to explain the mechanisms of toxicity of chemicals [46,100,101]. For Q67, which is increasingly used in monitoring environmental pollution and assessing toxicity, the luminescent inhibition rate for luminescent bacteria is always used as the endpoint.…”

Section: Homologous Model and Its Application In Q67mentioning

confidence: 99%

Protein Model and Function Analysis in Quorum-Sensing Pathway of Vibrio qinghaiensis sp.-Q67

Wang

et al. 2021

Biology

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Bioluminescent bacteria are mainly found in marine habitats. Vibrio qinghaiensis sp.-Q67 (Q67), a nonpathogenic freshwater bacterium, has been a focus due to its wide use in the monitoring of environmental pollution and the assessment of toxicity. However, the lack of available crystal structures limits the elucidation of the structures of the functional proteins of the quorum-sensing (QS) system that regulates bacterial luminescence in Q67. In this study, 19 functional proteins were built through monomer and oligomer modeling based on their coding proteins in the QS system of Q67 using MODELLER. Except for the failure to construct LuxM due to the lack of a suitable template, 18 functional proteins were successfully constructed. Furthermore, the relationships between the function and predicted structures of 19 functional proteins were explored one by one according to the three functional classifications: autoinducer synthases and receptors, signal transmission proteins (phosphotransferases, an RNA chaperone, and a transcriptional regulator), and enzymes involved in bacterial bioluminescence reactions. This is the first analysis of the whole process of bioluminescence regulation from the perspective of nonpathogenic freshwater bacteria at the molecular level. It provides a theoretical basis for the explanation of applications of Q67 in which luminescent inhibition is used as the endpoint.

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In silico toxicity evaluation of Salubrinal and its analogues

Cited by 17 publications

References 138 publications

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Salubrinal Regulates the Apoptosis of Adrenocortical Carcinoma Cells via the PERK/eIF2α/ATF4 Signaling Pathway

Protein Model and Function Analysis in Quorum-Sensing Pathway of Vibrio qinghaiensis sp.-Q67

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