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

Abstract

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.

Pharmacophore model-aided virtual screening combined with comparative molecular docking and molecular dynamics for identification of marine natural products as SARS-CoV-2 papain-like protease inhibitors

“…DCCM and PCA of MD trajectories are complementary to RMSD and RMSF in analysing the essential dynamics of proteins during ligand binding. Recent studies have utilized DCCM and PCA to analyse the protein motions in the ligand-bound form ( Bharadwaj et al, 2021 , Shafie et al, 2021 ). DCCM quantified the dynamics of Cα-atoms movements from the final 50ps of MD trajectories.…”

Phenolic Composition, Wound Healing, Antinociceptive, and Anticancer Effects of Caralluma europaea Extracts

“…The molecular docking of Lavandula officinalis phytocompounds showed a glide score energy between −4.596 and −5.34 kcal/mol in the active site of casein kinase-1, and a glide score energy between −6.298 and −7.652 kcal/mol in the active site of glycogen synthase kinase-3β [ 29 ]. Another study targeted CK1 in the same active site, hence the importance of this active site to target this protein [ 30 ].…”

Identification of mitogen‐activated protein kinase 7 inhibitors from natural products: Combined virtual screening and dynamic simulation studies

“…Each system was placed 10 Å apart from each side of a cube‐shaped box. The model was hydrated in the aquatic medium using the SPC216 model 49 . A required number of counterions were successfully added to maintain the electrically balanced system.…”

“…The model was hydrated in the aquatic medium using the SPC216 model. 49 A required number of counterions were successfully added to maintain the electrically balanced system. Steepest descent is an iterative method employed to minimize the energy of all the systems.…”