Curcumin specifically binds to the human calcium–calmodulin-dependent protein kinase IV: fluorescence and molecular dynamics simulation studies

Abstract

Calcium-calmodulin-dependent protein kinase IV (CAMK4) plays significant role in the regulation of calcium-dependent gene expression, and thus, it is involved in varieties of cellular functions such as cell signaling and neuronal survival. On the other hand, curcumin, a naturally occurring yellow bioactive component of turmeric possesses wide spectrum of biological actions, and it is widely used to treat atherosclerosis, diabetes, cancer, and inflammation. It also acts as an antioxidant. Here, we studied the interaction of curcumin with human CAMK4 at pH 7.4 using molecular docking, molecular dynamics (MD) simulations, fluorescence binding, and surface plasmon resonance (SPR) methods. We performed MD simulations for both neutral and anionic forms of CAMK4-curcumin complexes for a reasonably long time (150 ns) to see the overall stability of the protein-ligand complex. Molecular docking studies revealed that the curcumin binds in the large hydrophobic cavity of kinase domain of CAMK4 through several hydrophobic and hydrogen-bonded interactions. Additionally, MD simulations studies contributed in understanding the stability of protein-ligand complex system in aqueous solution and conformational changes in the CAMK4 upon binding of curcumin. A significant increase in the fluorescence intensity at 495 nm was observed (λexc = 425 nm), suggesting a strong interaction of curcumin to the CAMK4. A high binding affinity (KD = 3.7 × 10(-8) ± .03 M) of curcumin for the CAMK4 was measured by SPR further indicating curcumin as a potential ligand for the CAMK4. This study will provide insights into designing a new inspired curcumin derivatives as therapeutic agents against many life-threatening diseases.

Binding studies and biological evaluation of β-carotene as a potential inhibitor of human calcium/calmodulin-dependent protein kinase IV

“…(Table 2). These results are consistent with curcumin, a natural anticancer molecule used as a positive control in this study [25]. It is noteworthy that β-carotene has a significant anticancer activity against hepatic cancer cell line, which bears lowest IC 50 value (41.52 μM) as shown in Fig 4B. …”

“…As CAMKIV is the responsible factor for neurodegenerative diseases and varieties of cancer, it could be considered a new target for the structure-based drug designing [25,26]. STO609, KN-93 [27] and KN-62 [28] are reported kinase inhibitors.…”

Chitinase from Thermomyces lanuginosus SSBP and its biotechnological applications

“…MD simulations can track system behavior and understanding of protein folding (Ubaid-Ullah et al 2014;Haque et al 2015;Naiyer et al 2015). These methods are used to investigate the structure, dynamics and thermodynamics of biological molecules (Anwer et al 2015;Hoda et al 2015;Naz et al 2015). In explicit conditions, all atoms of a protein and surrounding water molecules move in a series of time steps.…”

Hesperidin‐CAMKIV interaction and its impact on cell proliferation and apoptosis in the human hepatic carcinoma and neuroblastoma cells

“…However, hesperidin did not show any growth‐inhibiting effect on HEK293 cells even up to > 200 μM concentration (Figure ), demonstrating its nontoxic nature against normal cells. Likewise, we have used a natural anticancer molecule, that is, curcumin as a positive control in this study (data not shown) . Collectively, these results indicate that hesperidin may possess antiproliferative activity and inhibits the HepG2 and SH‐SY5Y cells proliferation.…”