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

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'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.

Automated summary

In this study, three phytoconstituents, Semiglabrinol, Curcusone A, and Liriodenine, were identified as potential inhibitors of CK1 alpha with considerable affinity and specificity, stabilizing the protein and reducing conformational fluctuations. Molecular dynamics simulations and MM-PBSA analysis further confirmed the strong binding affinity of these compounds towards CK1 alpha.