In Silico and In Vitro Screening of 50 Curcumin Compounds as EGFR and NF-κB Inhibitors

Abstract

The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition

“…No. 12054-H09E, Sino Biological Europe GmbH, Eschborn, Germany), and the labeling was performed as previously described [ 53 ]. Serial dilutions from 300,000 to 100 nM of jozimine A 2 and michellamine B were incubated for 30 min at room temperature (RT) with the labeled human recombinant NF-κB protein in a 1:1 ratio.…”

Curcumin in Cancer and Inflammation: An In-Depth Exploration of Molecular Interactions, Therapeutic Potentials, and the Role in Disease Management

“…In their research, Mohamed EM Saeed and colleagues conducted a comprehensive molecular docking study involving 50 curcumin derivatives, sourced from the PubChem database [ 107 ]. These compounds were analyzed for their binding affinity with NF-κB.…”

Therapeutic potential and limitations of curcumin as antimetastatic agent

“…On the other hand, curcumin, unlike tetrahydrocurcumin, can directly interact with the STAT3 SH2 domain, suppress its dimerization and subsequent nuclear translocalization [215]. In the case of curcumin sulfate and glucuronide curcumin, their possible inhibitory effects against EGFR and NF-KB cannot be excluded [216] Nevertheless, glucuronide curcumin could have significantly lower cellular uptake compared to natural curcumin. Jamil et al reported, that MDBA-231 human breast cancer cells can metabolize curcumin to curcumin sulphate and subsequently excrete it from the cells [217].…”