Binding mechanism of caffeic acid and simvastatin to the integrin linked kinase for therapeutic implications: a comparative docking and MD simulation studies

Gulzar, M. Saeed; Ali, Shahid; Khan, Faez Iqbal; Κhan, Parvez; Taneja, Pankaj; Hassan, Md. Imtaiyaz

doi:10.1080/07391102.2018.1546621

Cited by 54 publications

(23 citation statements)

References 58 publications

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“…To understand the physical basis of the structure and function of biological macromolecules, MD simulation substantiates to be an essential approach (Amir et al, 2020 ; Beg et al, 2019 ; Dahiya et al, 2019 ; Gulzar et al, 2019 ; Gupta et al, 2019 ; Gupta et al, 2019 ). This technique assists in discovering the structural dynamics and how it is coupled to the biomolecular function of the enzyme (McCammon et al, 1977 ; Karplus & McCammon, 2002 ; Arnittali et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

Khan

Fakhar

Hussain

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Section: Methodsmentioning

confidence: 99%

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

Khan

Fakhar

Hussain

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…Any small molecule can induce a large conformational change in a protein after binding [26][27][28][29]. Root-mean-square deviation (RMSD) is an important approach to estimate the structural deviation and stability of a protein structure [30][31][32][33][34][35].…”

Section: Structural Deviation and Compactnessmentioning

confidence: 99%

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

et al. 2019

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Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation.

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“…Most of the protein kinase inhibitors isolated from plants are polyphenols, mainly belonging to flavonoids [ 19 – 21 , 27 , 28 ]. However, there are representatives of nonflavonoids also that show inhibitory effects for human kinases, including resveratrol, caffeic acid, and gallic acid [ 29 , 30 ]. Our previous studies demonstrated the binding and inhibition of CaMKIV by various natural compounds including hesperidin, β -carotene, and vanillin [ 31 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential Inhibitors of Calcium/Calmodulin-Dependent Protein Kinase IV from Bioactive Phytoconstituents

Gupta

Khan

Fakhar

et al. 2020

Oxidative Medicine and Cellular Longevity

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Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is an upstream regulator of CaMKK-CaMKIV signaling cascade that activates various transcription factors, thereby regulating several cellular activities including, neuronal communication and immune response. Owing to the abnormal expression in cancer and neurodegenerative diseases, the CaMKIV has been considered a potential drug target. In the present study, we checked the binding affinity of plant-derived natural compounds viz., quercetin, ellagic acid (EA), simvastatin, capsaicin, ursolic acid, DL-α-tocopherol acetate, and limonin towards CaMKIV. Molecular docking and fluorescence binding studies showed that EA and quercetin bind to the CaMKIV with a considerable affinity in comparison to other compounds. Enzyme inhibition assay revealed that both EA and quercetin inhibit CaMKIV activity with their IC50 values in the micromolar range. To get atomistic insights into the mode of interactions, inhibition mechanism, and the stability of the CaMKIV-ligand complex, a 100 ns MD simulation analysis was performed. Both EA and quercetin bind to the catalytically important residues of active site pocket of CaMKIV forming enough stabilizing interactions presumably inhibiting enzyme activity. Moreover, no significant structural change in the CaMKIV was observed upon binding of EA and quercetin. In conclusion, this study illustrates the application of phytoconstituents in the development of therapeutic molecules targeting CaMKIV having implications in cancer and neurodegenerative diseases after in vivo validation.

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Binding mechanism of caffeic acid and simvastatin to the integrin linked kinase for therapeutic implications: a comparative docking and MD simulation studies

Cited by 54 publications

References 58 publications

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

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

Identification of Potential Inhibitors of Calcium/Calmodulin-Dependent Protein Kinase IV from Bioactive Phytoconstituents

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