In silico screening and study of novel ERK2 inhibitors using 3D QSAR, docking and molecular dynamics

Larif, S.; Salem, Chaker Ben; Hmouda, Houssem; Bouraoui, Kamel

doi:10.1016/j.jmgm.2014.07.001

Cited by 10 publications

(4 citation statements)

References 36 publications

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“…An in silico study demonstrated that 22-(4 py)-JA could interact with ERK1, ERK2 and MEK1, especially at the kinase domain. All of the interactions showed the great potency of 22-(4 py)-JA as an inhibitor of the MAPK family, for which the binding energy was lower than -5 Kcal/mol [43]. Based on our findings, in silico and in vitro preclinical evaluations verified that ERK1/2 and MEK1 are molecular targets of 22-(4 py)-JA in inducing NSCLC apoptosis.…”

Section: Discussionsupporting

confidence: 56%

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

et al. 2022

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A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

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Section: Discussionsupporting

confidence: 56%

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

et al. 2022

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“…Interestingly, only a few in silico investigations on the ERK inhibitors have been reported so far. These investigations were based on in silico methods such as 2D/3D-quantitative structure–activity relationships (2D/3D-QSAR), molecular docking, molecular dynamics simulations, etc [21,22,23]. However, these in silico investigations were performed with one of the isoforms of ERK and the number, as well as the structural diversity of the data points considered, have been also limited.…”

Section: Introductionmentioning

confidence: 99%

Multi-Target Chemometric Modelling, Fragment Analysis and Virtual Screening with ERK Inhibitors as Potential Anticancer Agents

2019

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Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer. The ERK-1/2 inhibitors are thus considered as potential agents for cancer therapy. Multitarget quantitative structure–activity relationship (mt-QSAR) models based on the Box–Jenkins approach were developed with a dataset containing 6400 ERK inhibitors assayed under different experimental conditions. The first mt-QSAR linear model was built with linear discriminant analysis (LDA) and provided information regarding the structural requirements for better activity. This linear model was also utilised for a fragment analysis to estimate the contributions of ring fragments towards ERK inhibition. Then, the random forest (RF) technique was employed to produce highly predictive non-linear mt-QSAR models, which were used for screening the Asinex kinase library and identify the most potential virtual hits. The fragment analysis results justified the selection of the hits retrieved through such virtual screening. The latter were subsequently subjected to molecular docking and molecular dynamics simulations to understand their possible interactions with ERK enzymes. The present work, which utilises in-silico techniques such as multitarget chemometric modelling, fragment analysis, virtual screening, molecular docking and dynamics, may provide important guidelines to facilitate the discovery of novel ERK inhibitors.

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“…maybridge.com) with over 53,000 compounds and Chembank database (Seiler et al, 2008). Top screened compounds were then subjected to molecular docking that identified new scaffolds with high potency and selectivity against ERK2 (Larif et al, 2014).…”

Section: Ligand-based Methods In Drug Designmentioning

confidence: 99%

In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

et al. 2020

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Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies.

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In silico screening and study of novel ERK2 inhibitors using 3D QSAR, docking and molecular dynamics

Cited by 10 publications

References 36 publications

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

Multi-Target Chemometric Modelling, Fragment Analysis and Virtual Screening with ERK Inhibitors as Potential Anticancer Agents

In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

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