Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

Batra, Sagar; Dahiya, Rashmi; Baig, Mohammad Hassan; Rather, Irfan A.; Dong, Jae-June; Hassan, Imtaiyaz

doi:10.3390/molecules24244589

Cited by 47 publications

(25 citation statements)

References 54 publications

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“…4j and 4k thus can act as ATP competitive type II inhibitor by binding to inactive kinase [ 61 ]. Moreover, both the compounds showed a similar fashion of interactions, which involved several hydrogen bonds and ionic interactions with the binding site cavity surrounding residues, such as Ile10, Val18, Ala31, Val64, Glu81, Phe82, Leu134 and Ala144, which is consistent with the molecular docking analysis of 3,6-disubstituted pyridazines; 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine as CDK2 inhibitors (2, 3) [ 62 , 63 ]. However, compound 4j formed one additional interaction with Lys89, which was absent in case of compound 4k .…”

Section: Resultssupporting

confidence: 71%

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

et al. 2020

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Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC50 = 1.51 ± 0.09 µM) and 4k (IC50 = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC50 = 5.46 ± 0.71 µM) and A2780 (IC50 = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC50 = 0.245 µM) and 4k (IC50 = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC50 = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.

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Section: Resultssupporting

confidence: 71%

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

et al. 2020

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“…The therapeutic potential of these plant-based products has been explored in terms of their kinase targeting capabilities. 23 − 27 Around 80% of the population still relies on plant-derived formulations to manage different medical issues. 19 In recent years, there is a switch in the screening and discovery of natural products as potential kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

et al. 2020

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Cyclin-dependent kinase 6 (CDK6) is a potential drug target that plays an important role in the progression of different types of cancers. We performed in silico and in vitro screening of different natural compounds and found that quercetin has a high binding affinity for the CDK6 and inhibits its activity with an IC 50 = 5.89 μM. Molecular docking and a 200 ns whole atom simulation of the CDK6-quercetin complex provide insights into the binding mechanism and stability of the complex. Binding parameters ascertained by fluorescence and isothermal titration calorimetry studies revealed a binding constant in the range of 10 7 M –1 of quercetin to the CDK6. Thermodynamic parameters associated with the formation of the CDK6–quercetin complex suggested an electrostatic interaction-driven process. The cell-based protein expression studies in the breast (MCF-7) and lung (A549) cancer cells revealed that the treatment of quercetin decreases the expression of CDK6. Quercetin also decreases the viability and colony formation potential of selected cancer cells. Moreover, quercetin induces apoptosis, by decreasing the production of reactive oxygen species and CDK6 expression. Both in silico and in vitro studies highlight the significance of quercetin for the development of anticancer leads in terms of CDK6 inhibitors.

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“…For overall conformation and stability of enzyme structure, we have measured the intramolecular and intermolecular hydrogen bond analysis ( Figure 6). This analysis gives extreme understanding into binding mechanism of enzyme-ligand with detailed consideration [55]. An average number of intramolecular hydrogen bonds in ABBV-744-M pro complex was noted to be 136 as displayed in Figure 6A.…”

Section: Hydrogen Bond Analysismentioning

confidence: 90%

ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

Fakhar¹,

Khan²,

Ahmad³

2020

Preprint

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A new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening work-flow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the best hit compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered compounds. Binding studies revealed that compound ABBV-744 binds to the Mpro with strong affinity (Gbind -45.43 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

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Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

Cited by 47 publications

References 54 publications

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

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