Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations

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dc.contributor.authorShafie, Alaa
dc.contributor.authorKhan, Shama
dc.contributor.authorZehra
dc.contributor.authorMohammad, Taj
dc.contributor.authorAnjum, Farah
dc.contributor.authorHasan, Gulam Mustafa
dc.contributor.authorYadav, Dharmendra Kumar
dc.contributor.authorHassan, Md. Imtaiyaz
dc.date.accessioned2022-04-04T07:17:41Z
dc.date.available2022-04-04T07:17:41Z
dc.date.issued2021-12-15
dc.date.updated2021-12-23T15:06:30Z
dc.description.abstractCasein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α.en_US
dc.identifierdoi: 10.3390/pharmaceutics13122157
dc.identifier.apacitationShafie, A., Khan, S., , Mohammad, T., Anjum, F., Hasan, G. M., ... Hassan, Md. Imtaiyaz. (2021). Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations. <i>Pharmaceutics</i>, 13(12), 2157. http://hdl.handle.net/11427/36252en_ZA
dc.identifier.chicagocitationShafie, Alaa, Shama Khan, , Taj Mohammad, Farah Anjum, Gulam Mustafa Hasan, Dharmendra Kumar Yadav, and Md. Imtaiyaz Hassan "Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations." <i>Pharmaceutics</i> 13, 12. (2021): 2157. http://hdl.handle.net/11427/36252en_ZA
dc.identifier.citationShafie, A., Khan, S., , Mohammad, T., Anjum, F., Hasan, G.M., Yadav, D.K. & Hassan, Md. Imtaiyaz. et al. 2021. Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations. <i>Pharmaceutics.</i> 13(12):2157. http://hdl.handle.net/11427/36252en_ZA
dc.identifier.ris TY - Journal Article AU - Shafie, Alaa AU - Khan, Shama AU - Zehra AU - Mohammad, Taj AU - Anjum, Farah AU - Hasan, Gulam Mustafa AU - Yadav, Dharmendra Kumar AU - Hassan, Md. Imtaiyaz AB - Casein kinase-1 alpha (CK1&alpha;) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1&alpha; family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1&alpha; in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1&alpha;. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski&rsquo;s rules and PAINS filter. Further, high-affinity hits against CK1&alpha; were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1&alpha; binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1&alpha; and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1&alpha;. DA - 2021-12-15 DB - OpenUCT DP - University of Cape Town IS - 12 J1 - Pharmaceutics KW - casein kinase-1 alpha KW - phytoconstituents KW - drug discovery KW - virtual screening KW - molecular dynamics simulation KW - dynamical cross-correlation matrices KW - principal components analysis LK - https://open.uct.ac.za PY - 2021 T1 - Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations TI - Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations UR - http://hdl.handle.net/11427/36252 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/36252
dc.identifier.vancouvercitationShafie A, Khan S, , Mohammad T, Anjum F, Hasan GM, et al. Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations. Pharmaceutics. 2021;13(12):2157. http://hdl.handle.net/11427/36252.en_ZA
dc.language.isoenen_US
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePharmaceuticsen_US
dc.source.journalissue12en_US
dc.source.journalvolume13en_US
dc.source.pagination2157en_US
dc.source.urihttps://www.mdpi.com/journal/pharmaceutics
dc.subjectcasein kinase-1 alphaen_US
dc.subjectphytoconstituents
dc.subjectdrug discovery
dc.subjectvirtual screening
dc.subjectmolecular dynamics simulation
dc.subjectdynamical cross-correlation matrices
dc.subjectprincipal components analysis
dc.titleIdentification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulationsen_US
dc.typeJournal Articleen_US
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