Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations
Casein 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...
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MDPI AG
2021-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/12/2157 |
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| author | Alaa Shafie Shama Khan Zehra Taj Mohammad Farah Anjum Gulam Mustafa Hasan Dharmendra Kumar Yadav Md. Imtaiyaz Hassan |
| author_facet | Alaa Shafie Shama Khan Zehra Taj Mohammad Farah Anjum Gulam Mustafa Hasan Dharmendra Kumar Yadav Md. Imtaiyaz Hassan |
| author_sort | Alaa Shafie |
| collection | DOAJ |
| description | Casein 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. |
| first_indexed | 2024-03-10T03:19:03Z |
| format | Article |
| id | doaj.art-02c52027d8424279bc3d3903dabab62b |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:19:03Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-02c52027d8424279bc3d3903dabab62b2023-11-23T10:06:41ZengMDPI AGPharmaceutics1999-49232021-12-011312215710.3390/pharmaceutics13122157Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics SimulationsAlaa Shafie0Shama Khan1Zehra2Taj Mohammad3Farah Anjum4Gulam Mustafa Hasan5Dharmendra Kumar Yadav6Md. Imtaiyaz Hassan7Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaDrug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South AfricaDepartment of Computer Science, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaDepartment of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi ArabiaCollege of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro, Yeonsu-gu, Incheon City 21924, KoreaCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaCasein 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.https://www.mdpi.com/1999-4923/13/12/2157casein kinase-1 alphaphytoconstituentsdrug discoveryvirtual screeningmolecular dynamics simulationdynamical cross-correlation matrices |
| spellingShingle | Alaa Shafie Shama Khan Zehra Taj Mohammad Farah Anjum Gulam Mustafa Hasan Dharmendra Kumar Yadav Md. Imtaiyaz Hassan Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations Pharmaceutics casein kinase-1 alpha phytoconstituents drug discovery virtual screening molecular dynamics simulation dynamical cross-correlation matrices |
| title | Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations |
| title_full | Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations |
| title_fullStr | Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations |
| title_full_unstemmed | Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations |
| title_short | Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations |
| title_sort | identification of phytoconstituents as potent inhibitors of casein kinase 1 alpha using virtual screening and molecular dynamics simulations |
| topic | casein kinase-1 alpha phytoconstituents drug discovery virtual screening molecular dynamics simulation dynamical cross-correlation matrices |
| url | https://www.mdpi.com/1999-4923/13/12/2157 |
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