NUTRIGENOMIC STUDY ON CURCUMIN.

A COMPUTATIONAL APPROACH
Radu TAMAIAN 1
Laurent-Emmanuel MONFOULET 2
Christine MORAND 2
Dragan MILENKOVIC 2,3
Nutrigenomics
• Nutrigenomics therefore initially referred to the study of the
effects of nutrients on the expression of an individual’s
genetic makeup. More recently, this definition has been
broadened to encompass nutritional factors that protect the
genome from damage.
• Ultimately, nutrigenomics is concerned with the impact of
dietary components on the genome, the proteome (the sum
total of all proteins), and the metabolome (the sum of all
metabolites).
• As in pharmacogenomics, researchers recognize that only a
portion of the population will respond positively to specific
nutritional interventions, while others will be unresponsive or
even be adversely affected. Nutrigenomics: The Genome–Food Interface
M. Nathaniel Mead.
Environmental Health Perspectives, 2007, 115(12): A582–A589
 Curcumin
(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione

Curcumin is a plant Curcumin modulates signaling molecules!

phenolic and the principal
curcuminoid of turmeric
(Curcuma longa).

The beneficial role of curcumin on inflammation, diabetes and

neurodegenerative disease: A recent update
S. Ghosh, S. Banerjee, P.C. Sil.
Food and Chemical Toxicology, 2015, 83:111-124
Aim
• This study aimed to evaluate all the possible interactions and
the binding affinity (BA) of curcumin for cell-signaling proteins
of the NF-𝜿B signaling pathway in order to reveal the
underlying mechanism of its nutrigenomic effects.

• NF-𝜿B (nuclear factor kappa-light-chain-enhancer of activated

B cells) is a protein complex that controls transcription of
DNA, cytokine production and cell survival.
 NF-𝜿B pathway
• Nuclear factor-𝜿B (NF-𝜿B)/Rel
proteins include: NF-𝜿B2
p52/p100, NF-𝜿B1 p50/p105,
c-Rel, RelA/p65 and RelB.
• These proteins function as
dimeric transcription factors
that regulate the expression
of genes influencing a broad
range of biological processes
including innate and adaptive
immunity, inflammation,
stress responses, B-cell
development and lymphoid
organogenesis.
https://www.cellsignal.com/contents/science-cst-pathways-immunology-and-inflammation/nf-b-signaling-interactive-pathway/pathways-nfkb
 Molecular Docking
Garrett M. Morris, Marguerita Lim-Wilby.
Molecular Modeling of Proteins, 2008, 443:365-382
Part of the Methods Molecular Biology™ book series (MIMB, vol. 443)

Methodology
• Docking (molecular docking) is a key tool in structural biology
and computer-assisted drug design (CADD).
• The goal of ligand-protein docking is to predict the predominant
binding mode(s) of a ligand with a protein (with known or
predicted 3D structure).
• Docking analysed the formation of the binding complex in order
to identify most probable curcumin/proteins interaction.
 Identification
Selection criteria

Targets • Method: X-ray

• Resolution: < 2.0Å
• Coverage: > 90%

Protein Classification (according to UniProt) UniProt ID 3D structure[*]

TRAF2 TNF receptor-associated factor family Q12933 HM based on 1CA9
PDPK1 Protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily O15530 HM based on 2BIY
AKT1 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily P31749 HM based on 4EJN
AKT2 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily P31751 HM based on 4EJN
AKT3 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily Q9Y243 HM based on 4EJN
TAK1 Protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily O43318 HM based on 5GJF
I𝜿Kα Protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily O15111 HM based on 5EB
I𝜿Kβ Protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily O14920 HM based on 4E3C
I𝜿Kɣ Protein family membership (no subfamily assigned) Q9Y6K9 HM based on 4UXV
I𝜿Bα NF-kappa-B inhibitor family P25963 HM based on 1NFI
I𝜿Bβ NF-kappa-B inhibitor family Q15653 HM based on 1OY3
NF𝜿B (p65) Transcription factor Q04206 HM based on 1NFI
Rel B Transcription factor Q01201 HM based on 1NFI
[*]
Constructed homologues models (HM) with the help of SWISS-MODEL,
based on PDB crystal structures
 Small-Molecule Library Screening by Docking with PyRx
Sargis Dallakyan, Arthur J. Olson.
Chemical Biology, 2015, 1263:243-250
Part of the Methods Molecular Biology™ book series (MIMB, vol. 1263)

Docking setup
• Docking of curcumin against the
selected targets was conducted with
PyRx – Python Prescription using
AutoDock Vina as docking
software/algorithm.
• AutoDock Vina automatically calculates
the grid maps, predicts the noncovalent
binding of macromolecules and clusters
the results.
• All docking runs were conducted as AutoDock Vina: improving the speed and accuracy of docking with a
new scoring function, efficient optimization and multithreading
“blind” docking and the exhaustiveness Oleg Trott, Arthur J. Olson.
Journal of Computational Chemistry, 2010, 31(2): 455-461
was manually increased to 80 (10 times
from default value of PyRx) in order to Blind docking of drug-sized compounds to proteins with up to a
thousand residues
Csaba Hetényi, David van der Spoel.
improve the accuracy of predictions. FEBS Letters, 2006, 580(5):1447-1450
 Results & discussion
The predicted binding affinity (BA)
BA
Protein Classification (according to UniProt)
(kcal/mol)
TRAF2 TNF receptor-associated factor family -6.0
PDPK1 Protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily -7.3
AKT1 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily -9.4
AKT2 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily -9.3
AKT3 Protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily -8.8
TAK1 Protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily -7.9
I𝜿Kα Protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily -7.1
I𝜿Kβ Protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily -8.0
I𝜿Kɣ Protein family membership (none subfamily assigned) -6.9
I𝜿Bα NF-kappa-B inhibitor family -6.0
I𝜿Bβ NF-kappa-B inhibitor family -6.9
NF𝜿B (p65) Transcription factor -6.4
Rel B Transcription factor -6.1
RED: weak interactions
GREEN: strong interactions
 Best docking pose of
CURCUMIN against AKT1

Energy grid:
green – steric favorable
light blue – H acceptor favorable
yellow – H donor favorable
orange to red and blue – electrostatic interactions
Results & discussion
• Kinases: interactions are made with the protein kinase domain
• TRAF2: interactions are made with MATH domain (1)
• I𝜿Bα: interactions are made with Repeats ANK 3 and ANK 4 (2)
• I𝜿Bβ: interactions are made with Repeat ANK 1 (3)
• I𝜿Kɣ: interactions are made with TANK region (4)
• Transcription factors: interactions are made with the RHD domain (5)
Conclusions
• The interactions of curcumin with the NF-𝜿B pathway is
supported by our results obtained in silico that revealed
favourable antagonistic strong binding of curcumin to RAC
subfamily kinases (ATK 1-3) => inhibitory effects.
• Curcumin has a moderate BA for the other kinases (PDPK1,
TAK1, I𝜿Kα and I𝜿Kβ) => lesser biological significance.

• Modulation of endothelial permeability and monocyte

transendothelial migration by affecting endothelial cell
dynamics.
FA 1403 – POSITIVe (https://www6.inra.fr/cost-positive):
Interindividual variation in response to consumption of plant food bioactives and determinants involved

IF: 5.606

PN-III-P1-1.1-PRECISI-
2017-19884
1 st Zone

OVERVIEW OF THE DEMONSTRATED AND PUTATIVE MECHANISMS BY WHICH CURCUMIN CAN MODULATE ENDOTHELIAL CELL ACTIVATION
L.E. Monfoulet, S. Mercier, D. Bayle, R. Tamaian, N. Barber-Chamoux, C. Morand, D. Milenkovic. Curcumin modulates endothelial permeability and monocyte
transendothelial migration by affecting endothelial cell dynamics. Free Radical Biology & Medicine. 2017. 112:109-120. DOI: 10.1016/j.freeradbiomed.2017.07.019