The role of serum and glucocorticoid-regulated kinase 1 in cellular signaling: Implications for drug development.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a ubiquitously expressed protein belonging to the Ser/Thr kinase family. It regulates diverse physiological processes, including epithelial sodium channel activity, hypertension, cell proliferation, and insulin sensitivity. Due to its significant role in the pathogenesis of numerous diseases, SGK1 can be exploited as a potential therapeutic target to address challenging health problems. SGK1 is associated with the development of obesity, and its overexpression enhances the sodium-glucose co-transporter 1 activity, which absorbs intestinal glucose. This review highlighted the detailed functional significance of SGK1 signaling and role in different diseases and subsequent therapeutic targeting. We aim to provide deeper mechanistic insights into understanding the pathogenesis and recent advancements in the SGK1 targeted drug development process. Small-molecule inhibitors are being developed with excellent binding affinity and improved SGK1 inhibition with desired selectivity. We have discussed small molecule inhibitors designed explicitly as potent SGK1 inhibitors and their therapeutic implications in various diseases. We further addressed the therapeutic potential and mechanism of action of these SGK1 inhibitors and provided a strong scientific foundation for developing effective therapeutics.

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

Integrin linked kinase (ILK) is a Ser/Thr kinase, which regulates various integrin mediated signaling pathways, and is involved in cell adhesion, migration and differentiation. Alteration in the ILK is responsible for abnormal functioning of the cell system, which may lead to the cancer progression and metastasis. Caffeic acid (CA) and simvastatin are used as antioxidant and possess anticancer properties. Thus, inhibiting the kinase activity of ILK by CA and simvastatin may be implicated in the cancer therapy. In this study, we have performed molecular docking followed by 100 ns MD simulations to understand the interaction mechanism of ILK protein with the CA and simvastatin. Average potential energy was found to be highest in case of ILK-CA complex (-770,949 kJ/mol). Binding free energy was found to be higher in case of simvastatin than CA. Our results indicate that simvastatin binds more effectively to the active pocket of ILK. We further performed MTT assay to understand its anticancer potential. Simvastatin shows the IC50 values for HepG2 and MCF-7 as 19.18 ± 0.12 and 13.84 ± 0.22 µM, respectively. However, the IC50 value of CA on HepG2 and MCF-7 was reported as 175.50 ± 1.44 and 144.90 ± 1.53 µM, respectively. Our study provides a deeper insight into the binding mechanism of simvastatin and CA to ILK, which further opens a promising channel for their implications in cancer therapy.

Elucidation of interaction mechanism of ellagic acid to the integrin linked kinase.

Integrin-linked kinase (ILK) is a member of Ser/Thr kinase which interacts to the cytoplasmic domain of ß-integrins, and thereby induces apoptosis. ILK is considered as potential drug target because it's direct involvement in the tumor progression. Here, we have performed molecular docking followed by 100 ns MD simulation to understand the mechanism of interaction of ILK with the ellagic acid (EA). EA is well known for its antiproliferative and antioxidant properties in cancer cell lines and animal models. We have observed that EA binds to the active site cavity of ILK and causes conformational changes in the ILK structure. The orientation of EA in the active pocket of ILK showed to have least RMSD values and stable. The average binding energy ILK-EA complex calculated during MMPBSA was -191.267 kJ/mol, indicating a relatively strong binding affinity. The actual binding affinity of EA to ILK was measured by fluorescence spectroscopy and Kb and n values were 9.28 µM and 1.9264 (~2), respectively. The IC50 values for EA were 26.22 ±â€¯0.12 µM for MCF-7 and 38.45 ±â€¯2.42 µM for HepG2 cells, estimated by MTT assay. Our findings are helpful to design EA-based novel inhibitors of ILK which have potential to attenuate tumor progression.