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.

Autoren

Mohamed EM Saeed
Rümeysa Yücer
Mona Dawood
Mohamed-Elamir F Hegazy
Assia Drif
Edna Ooko
Onat Kadioglu
Ean-Jeong Seo
Fadhil S Kamounah
Salam J Titinchi
Beatrice Bachmeier
Thomas Efferth

DOI

10.3390/ijms23073966

eISSN

1422-0067

Ausgabe der Veröffentlichung

7

Zeitschrift

International Journal of Molecular Sciences

Sprache

en

Online publication date

2022

Paginierung

3966 - 3966

Status

Published online

Herausgeber

MDPI AG

Herausgeber URL

http://dx.doi.org/10.3390/ijms23073966

Datum der Datenerfassung

2023

Titel

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

Ausgabe der Zeitschrift

23

Data source: Crossref

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.

Addresses

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

Autoren

Mohamed EM Saeed
Rümeysa Yücer
Mona Dawood
Mohamed-Elamir F Hegazy
Assia Drif
Edna Ooko
Onat Kadioglu
Ean-Jeong Seo
Fadhil S Kamounah
Salam J Titinchi
Beatrice Bachmeier
Thomas Efferth

DOI

10.3390/ijms23073966

eISSN

1422-0067

Externe Identifier

PubMed Identifier: 35409325
PubMed Central ID: PMC9000198

Open access

true

ISSN

1422-0067

Ausgabe der Veröffentlichung

7

Zeitschrift

International journal of molecular sciences

Schlüsselwörter

Humans
Neoplasms
Curcumin
NF-kappa B
Ligands
I-kappa B Proteins
Molecular Docking Simulation
ErbB Receptors

Sprache

eng

Medium

Electronic

Online publication date

2022

Open access status

Open Access

Paginierung

3966

Datum der Veröffentlichung

2022

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2022

Titel

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

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

23

Files

https://www.mdpi.com/1422-0067/23/7/3966/pdf?version=1648890580 https://europepmc.org/articles/PMC9000198?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2022

Autoren

Mohamed EM Saeed
Rümeysa Yücer
Mona Dawood
Mohamed-Elamir F Hegazy
Assia Drif
Edna Ooko
Onat Kadioglu
Ean-Jeong Seo
Fadhil S Kamounah
Salam J Titinchi
Beatrice Bachmeier
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/35409325

DOI

10.3390/ijms23073966

eISSN

1422-0067

Externe Identifier

PubMed Central ID: PMC9000198

Ausgabe der Veröffentlichung

7

Zeitschrift

Int J Mol Sci

Schlüsselwörter

bioinformatics
cancer
natural products
phytochemicals
synthetic derivatives
virtual drug screening
Curcumin
ErbB Receptors
Humans
I-kappa B Proteins
Ligands
Molecular Docking Simulation
NF-kappa B
Neoplasms

Sprache

eng

Country

Switzerland

PII

ijms23073966

Datum der Veröffentlichung

2022

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2022

Titel

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

Sub types

Journal Article

Ausgabe der Zeitschrift

23

Data source: PubMed

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

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