In silico analysis of the anti-inflammatory activity of curcuminoids and/or curcumin metabolites on Cox-1 and Cox-2

doi:10.21203/rs.3.rs-4930657/v1

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In silico analysis of the anti-inflammatory activity of curcuminoids and/or curcumin metabolites on Cox-1 and Cox-2

https://doi.org/10.21203/rs.3.rs-4930657/v1

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Background

The present work involved a comparative in silico analysis of the action of curcuminoids and curcumin metabolites against cyclooxygenases 1 and 2. The Protein Data Bank (PDB) was used to obtain the target proteins and Discovery studio 2021, PyRx, ChemDraw Professional 16.0 or the PubChem search engine were used during in silico screening.

Results

The in silico analyses revealed that all the ligands analyzed form stable complexes with the Cox-1 and Cox-2 receptors, which are involved in anti-inflammatory activity. The complexation energy of the ligands with Cox-1 ranged from − 7.2 to -8.8 kcal/mol. The complexation energy of Cox-2 and the ligands analyzed ranged from − 5.2 to -6.4 kcal/mol, predicting a high affinity between the ligands analyzed and Cox-1 compared with Cox-2. In addition, the ligands analyzed formed thermodynamically stable complexes with Cox-1 in the majority of cases compared to the reference molecules analyzed (aspirin: -6.2 Kcal/mol and ibuprofen: -7.2 Kcal/mol). Bisdemethoxycurcumin, curcumin sulphate, curcumin, cyclocurcumin, demethoxycurcumin, dihydrocurcumin, hexahydrocurcumin and tetrahydrocurcumin formed very stable bonds with Cox-1 with interaction enthalpies of -8, 8 Kcal/mol, -8.7 Kcal/mol, -8.6 Kcal/mol, -8.3 Kcal/mol, -8.3 Kcal, -8.0 Kcal/mol, -7.9 Kcal/mol and − 7.8 Kcal/mol respectively. Moreover, most of the ligands analyzed formed thermodynamically stable bonds with Cox-2 compared with the reference molecules. The binding enthalpies were − 6.4 Kcal/mol, -6.1 Kcal/mol; -6.1 Kcal/mol, -5.9 Kcal/mol, -5.9 Kcal/mol, -5.7 Kcal/mol, -5.6 Kcal/mol and − 5.5 Kcal/mol for cyclocurcumin, bisdemethoxycurcumin, demethoxycurcumin, curcumin, curcumin sulphate, glucuronocurcumin, dihydrocurcumin and tetrahydrocurcumin respectively; compared with 4.5 Kcal/mol for the complex formed with aspirin and − 5.4 Kcal/mol for that formed with ibuprofen.

Conclusion

Curcuminoids can individually or synergistically inhibit the action of Cox and act as anti-inflammatory agents, curcumin metabolites can also bind to the catalytic sites of Cox 1 and 2 and compete with arachidonic acid, the natural substrate of Cox.

Curcuma longa

Curcuminoids

Metabolites

Cox 1

Cox 2

Anti-inflammatory

activity

In silico

Curcuma longa is a plant that has been used in food and traditional medicine for centuries [1–7]. The literature recommends C. longa for treating digestive problems, inflammatory diseases (rheumatoid, arthritis, osteoarthritis) and cardiovascular disorders, etc. [5, 8–19]. In addition, numerous scientific studies have shown that extracts of this plant have various pharmacological properties, mainly the anti-inflammatory activity [20–31]. These studies associate the pharmacological properties of turmeric with the presence of curcuminoids, which are flavonoids composed mainly of curcumin, demethoxycurcumin (DMC), bis-demothoxycurcumin (BDMC) and, to a lesser extent, cyclocurcumin [13, 20, 23–24, 28, 30, 32–33]. Although curcumin is indicated as the main biologically active molecule of C. longa [34–36]. It is the most important compound by weight, accounting for 50–60% of all curcuminoids, followed by DMC (24%) and BDMC (14%) [17, 23–24, 36–38].

According to Sandur et al. [2] and Alici et al. [13] turmeric marketed or used in research or clinical trials contains 77% pure curcumin (Cur), 17% of DMC and 3–6% of BDMC. Lee et al. [34] reported that curcuminoids contain approximately 71.5% of curcumin, 19.4% of DMC and 9.1% of BDMC.

Curcumin's anti-inflammatory activity is thought to be linked to the inhibition of arachidonic acid metabolism, which is metabolized to prostaglandins and leukotrienes respectively during the inflammation process by cyclo-oxygenase (Cox) and lipoxygenase (Lox) [39–42]. Several data in the literature have shown that Cox-1 and Cox-2 are involved in the production of prostaglandins (inflammatory mediators) and are therapeutic targets for most conventional anti-inflammatory drugs [43–48]. Hence the interest in conducting in silico investigations to show the potential of curcuminoids to inhibit Cox-1 and Cox-2. In silico studies revealing, comparatively, the action of curcuminoids against cyclooxygenases 1 and 2 are poor.

Meizarini et al. [28], showed in silico the activity of curcuminoids and particularly curcumin, DMC and BDMC against Cox-2 with free enthalpy of interactions values of -132,905 kcal/mol, -130,265 kcal/mol and − 118,827 kcal/mol respectively. Their screening also showed that C. longa extracts had anti-inflammatory activity by reducing the level of tumour necrosis factor (TNF) α expression. Sandur et al. [2] revealed that curcumin analogues, such as DMC, BDMC and tetrahydrocurcumin (THC), a curcumin metabolite, can modulate inflammatory signaling and cell proliferation signaling to the same extent as curcumin. These results showed that the potency of suppression of TNF induced nuclear factor kappaB (NF-kappaB) activation was significant for curcumin, followed by DMC and then BDMC, demonstrating the role of methoxy groups on the phenyl ring. Since THC had no conjugated bonds in the seven-carbon central chain, it was totally inactive in suppressing the transcription factor. They showed that suppression of NF-kappaB activity correlated with a decrease in Cox-2, cyclin D1 and vascular endothelial growth factor, all of which are regulated by NF-kappaB.

The literature also indicates that curcumin has poor absorption, low bioavailability in plasma and tissues, rapid hepatic metabolism and rapid systemic elimination in the intestine, with a peak human plasma concentration of 0.41 to 1.75 pmol/L [38, 49–50]. Hexahydrocurcumin, hexahydrocurcuminol, dyhydrocurcumin, tetrahydrocurcumin, glucurono-hexahydrocurcumin, glucuronocurcumin and sulpho-curcumin have been reported as the main metabolites of curcumin metabolism in the body [51–52]. These compounds are presented in most cases as inactive. Moreover, Sandur et al. [2] reported that THC, one of curcumin's metabolites, is more stable than curcumin and DMC. And that the two curcumin analogues mentioned above are less stable than BDMC. It should be noted that only few studies comparing the anti-inflammatory action of curcuminoids and curcumin metabolites in silico are reported. The aim of this study was to analyze the possible in silico interactions of curcumin metabolites with the catalytic sites of Cox-1 and Cox-2, in order to demonstrate their probable anti-inflammatory potential.

2.1. Activity against sickle cell disease in silico

2.1.1. Receptor preparation

Cox-1 and Cox-2, which are involved in the inflammation process, were used to assess the anti-inflammatory action of curcuminoids, including curcumin and its metabolites [53–55].

We used the Protein Data Bank website (https://www.rcsb.org/search) to obtain the 3D structures of the biological receptors used. The PDB IDs of cyclooxygenases 1 and 2 are 1eqg and 1cx2 respectively. After being uploaded to the database mentioned above, these receptors were stabilized by removing the hydrogen atoms in order to adjust them to human physiology. In addition, Discovery studio 2021 software was used to prepare and visualize the different residues present in the active site of these receptors [56]. The coordinates of the reference molecules (ibuprofen and aspirin) at 1eqg and 1cx2 were used to define the cyclooxygenase active site [57].

Figures 1.a and 1.b show the 2D structures of Cox-1 and Cox-2.

2.1.2. Preparation of ligands

The curcuminoids and curcumin metabolites used as ligands in this work were either drawn using ChemDraw Professional 16.0 software or downloaded from PubChem (http://pubchem.ncbi.nlm.nih.gov/). These ligands were saved in sdf format and then converted to mol2 format. This last step was preceded by a major potential energy minimization step involving the choice of force field. Our ligands were optimized using the UFF1 force field method, based on a semi-empirical approach, the aim of which is to optimize the geometry of the molecules and determine the energy and electronic distribution.

The structures of the curcuminoids and curcumin metabolites used are shown in Fig. 2.

2.2. Molecular docking

The biological receptors and ligands were imported into the PyRx software and then molecular docking was carried out using the Autodock Vina virtual screening tool [58–63]. This molecular docking concerned the region where the critical amino acids present in the cyclooxygenase active site are found. We used PyRx and Discovery studio 2021 software during molecular docking to determine the binding energy required to form a bond between each ligand and the biological receptor protein used, to visualize molecular docking, to analyze 2D hydrogen interactions of the receptor-ligand complex, to identify the residues present in the active sites of biological receptors, and to visualize and analyze 3D schematic representations of the structures of complexes formed between ligands and biological receptors [64–65]. The ranking score was evaluated in relation to the binding energy and then the nature of the bonds involved in the formation of ligand-receptor complexes [66]. The analyses were performed in triplicate.

3.1. In silico anti-inflammatory activity

The table below shows the complexation energy values of curcuminoids and its metabolites after in silico screening with Cox-1 and Cox-2 receptors:

Table 1

Free enthalpies of receptor-ligand interaction
Types of curcuminoids and curcumin metabolites	ΔG (kcal/moL) (n = 3)	ΔG (kcal/moL) (n = 3)
Types of curcuminoids and curcumin metabolites	Cox-1	Cox-2
1. Curcumin	-8.6 ± 0.28	-5.9 ± 0.15
2. Bisdemethoxycurcumin	-8.8 ± 0.05	-6.1 ± 0.05
3. Cyclocurcumin	-8.3 ± 0.00	-6.4 ± 0.00
4. Demethoxycurcumin	-8.3 ± 0.30	-6.1 ± 0.05
5. Dihydrocurcumine	-8.0 ± 1.15	-5.6 ± 0.05
6. Glucuronocurcumin or curcumin glucuronide	-8.2 ± 0.47	5.7 ± 0.11
7. Hexahydrocurcumin	-7.9 ± 0.15	-5.4 ± 0.11
8. Hexahydroxycurcuminol	-7.2 ± 0.40	-5.2 ± 0.05
9. Curcumin sulphate	-8.7 ± 0.17	-5.9 ± 0.17
10. Tetrahydrocurcumin	-7.8 ± 0.49	-5.5 ± 0.17
11. Aspirin (standard)	-6.2 ± 0.15	-4.5 ± 0.23
12. Ibuprofen (standard)	-7.2 ± 0.05	-5.4 ± 0.00

Apart from the docking score, the nature of the interactions between the ligands analyzed and the active receptor sites is an essential indication of the therapeutic potential of the compounds studied. Table 2 shows the amino acids and types of interaction involved in the formation of Cox-1 and Cox-2 complexes with ligands.

Table 2

Amino acids of Cox-1 and 2 involved in molecular interactions with curcumin, its derivatives or metabolites resulting from the degradation of curcumin
Types of curcuminoids and curcumin metabolites	Amino acids involved in interactions between ligands and biological receptors (Hb S)
	Cox-1	Cox-2
	Amino acids	Amino acids
1. Bisdemethoxy-curcumin (12)	Pro A : 136, Cys A :36 ; Cys A: 47; Pro A:153; Pro A: 40; Cys A: 31; GLN A: 461; Leu A:152; Gly A: 44; Arg A: 464; Lys A: 468; Asp A: 135; Tyr A: 339; Glu A: 465; GLN A: 42; His A: 43	Tyr A:115; Val A:116; Val A:89; Ile A:92; Val A:99; Val: 103; Leu A:93; Ile A:112; Trp A:100
2. Curcumin (13)	Asp A: 135; Tyr A: 136; Cys A: 36; Pro A: 156; Cys A: 47; Tyr A: 39; Arg A: 469; GLN A:44; His A: 43; Ile A:46; Tyr A: 130; Pro A: 153; Pro A: 40; Cys A: 41; GLN A: 461; Leu A: 152; Glu A: 465; Lys A: 468; GLN: 42	Val A:103; Val A:116; Leu A :111; Val A:99 ; Trp A :100 ; Phe A:96; Val A:89; Leu A:93; Ile A:92; Tyr A:115; Ile A:112
3. Cyclocurcumin (10)	Tyr A: 39; Cys A: 41; Glu A: 465; GLN A: 42; Lys A: 468; GLN A: 44; His A: 43; Thr A:62; Arg A: 79: Thr: A: 76; Gly A: 63; Tyr A:64; Thr A:80; Tyr A:64; Glyc A 471; Met A: 472; Arg A: 469; Gly A:45; Leu A:152	Val A:99; Ile A:112; Leu A :111 ; Ile A :92 ; Trp A :100 ; Leu A :93 ; Val :A :116 ; Tyr A :115
4. Demethoxycurcumin	GLN A:461; Ile: A:46; Tyr A:130; Gly A:45; Ile A:151; Arg A:469; His A:43; Leu A:152; Lys A:468; GLN A:42; Glu A:465; Pro A:156; Cys A:36; Cys A:47; Pro A:153; Tyr A:139; GLN A:44; Cys A:41	Trp 100; Ile A:92; Val A:89; Leu A:93; Leu A :111; Val A : 103 ; Val A :116 ; Ile A:112; Tyr A:115
5. Dihydrocurcumin	GLN A:461; Tyr A:99; Leu A :152 ; Glu A:465; Arg A:469; GLN A:44; Met A:472; His A:43; GLN A: 42; Pro A:474; Thr A:70; Pro A:72; Tyr A:64; Ile A:46; Cys A:47; Pro A:158; Cys A:41; Gly A:45; Lys A:468; Lys A 473	Trp A:100; Val A:89; Leu A:93; Val A:116; Leu A:111; Val A:99; Ile A:92; Ile A:112; Tyr A:112
6. Glucuronocurcumin	Ile A:46; Thr B:549; Ile A:137; Cys A:47; Tyr A:130; Cys A:41; Gly A:45; Lys A:468; GLN A:44; His A:43; GNL A: 42; Ser B:548; Trp: B:323; GNL B:327; Tyr A:136; Asp A:135; Val A:48; Pro A:153; Arg A:469; GLN A:461; Leu A: 152; Tyr A: 39; Glu A 465	Ile A:105; Leu A:108; Ser A :110 ; Lys A :111 ; Phe A :107 ; Leu A :111 ; Asn A :368 ; Glu A:364; Phe A:367
7. Hexahydrocurcumin	Ile A :46 ; Gly A:45; Leu A:152; Glu A:465; Arg A: 469; GLN A:44; Gly A:471: Lys; 473; Met A: 472; His A:43; Lys A:468; GLN A:42; Tyr A:39; GLN A:46; Pro A:153; Cys A:41; Cys A:36; Pro A:156; Cys A:47.	Leu A:111; Val A:89; Ile A : 92 ; Trp A :100 ; Leu A :93 ; Val A :99 ; Val A :103 ; Tyr A :115 ; Ile A :112 ; Val A :116; Leu A:108
8. Hexahydrocurcuminol	Lys A:473; Thr A:80; Arg A:79; Tyr A:64; His A:43; Gly A:45; Cys A:41; Tyr A:39; Leu A:152; Glu A:465; Lys A: 468; Arg A: 469; GLN A:44; GLN A:42; Gly A 471; Met A:472	Trp 100; Ile A:112; Leu A:111; Ile A :92 ; Val A :89 ; Leu A :99 ; Val A :116
9. Curcumin sulphate	Cys A:36; Tyr A:39; Glu A:465; GLN:461; GLN A:42; Gly A:471; Arg A:79; GLN A:44; Tyr A:64; Leu A:123; His A:43; Arg A:469; Lys A:468; Cys A:41; Ile A:46; Leu A:152; Pro A: 153; Tyr A:130; Cys A:47	Val A:99; Ile A:92; Val A : 89 ; Leu A :93 ; Val A :116 ; Tyr A :115 ; Lys A :114 ; Trp A:100; Ile A:112; Leu A:111
10. Tetrahydrocurcumin	Glu A: 465; Arg A: 469; Lys A: 468; GLN: A:44; Leu A:123; Gly A:471; Met A:472; Lys A: 473; His A:43; GLN A:42; Leu A:152; Cys A:41; Tyr A:39	Ile A:92; Leu A:93; Val A :89 ; Leu A :111 ; Val : 116 ; Val A :103 ; Leu A :108 ; Ile A : 112 ; Trp A :100 ; Tyr A :115
11. Reference 1 (Ibuprofen)	Ser A:154; Pro A:40; Cys A:41; Gly A:45; Gln A:42; His A:43; Gln A:44; Arg A:469; Leu A:152; Glu A:465; Cys A:47; Cys A:36; Gln A:461; Pro A:153; Tyr A:39; Pro A:156	Leu A:93; Ile A:92; Val A :89; Trp A :100; Ile A:112; Tyr A:115; Leu A:111
12. Reference 2 (Aspirin)	Cys A:47; Tyr A:39; Gln A:461; Pro A:153; Leu A:152; Lys A:468; Glu A:465; Arg A:469; Cys A:41; Gln A:42; His A:43; Gly A:45; Gln A:44	Tyr A:115; Ile A:112; Val A :116; Val A :89; Ile A:92; Trp A:100; Leu A:93

Legend: Amino acids in bold represent the Cox-1 and Cox-2 active site residues involved in their binding to the reference molecules studied and also to the ligands analyzed.

In addition, the structures of the complexes (in 2D) formed between Cox-1 or Cox-2 and curcumin, its derivatives and metabolites and also the types of interactions involved in the formation of these complexes are presented in Figs. 1.1 to 1.12 and Figs. 2.1 to 2.12).

4.1. In silico anti-inflammatory activity

4.1.1. Free enthalpies of receptor-ligand interaction

Curcuminoids and its metabolites form stable complexes with Cox-1 and Cox-2 receptors, which are involved in anti-inflammatory activity; in silico screening showed that in all cases the ΔG ˂ 0 (table 1). The free enthalpy of interaction values for the ligands analyzed with the Cox-1 receptor ranged from -7.2 to -8.8 kcal/mol, while those for the ligands analyzed with the Cox-2 receptor oscillated between -5.2 and -6.4 kcal/mol.

Concerning the Cox-1 receptor, the majority of ligands analyzed showed high thermodynamic stability compared to reference molecules (aspirin: -6.2 kcal/mol and ibuprofen: -7.2 kcal/mol). For these ligands, the decreasing order of ΔG is -8.8 Kcal/mol, -8.7 Kcal/mol, -8.6 Kcal/mol, -83 Kcal/mol, -8.3 Kcal, -8.0 Kcal/mol, -7.9 Kcal/mol and -7.8 Kcal/mol for bisdemethoxycurcumin, curcumin sulphate, curcumin, cyclocurcumin, demethoxycurcumin, dihydrocurcumin, hexahydrocurcumin and tetrahydrocurcumin respectively. These findings show that, in addition to curcumin and its derivatives (bisdemethoxycurcumin, cyclocurcumin and demethoxycurcumin), the metabolites of curcumin formed in the body (curcumin sulphate, dihydrocurcumin, hexahydrocurcumin and tetrahydrocurcumin) can also form thermodynamically stable bonds with Cox-1.

With regard to the Cox-2 receptor, analysis of the free enthalpy values showed that only cyclocurcumin, bisdemethoxycurcumin, demethoxycurcumin, curcumin, curcumin sulphate, glucuronocurcumin, dihydrocurcumin and tetrahydrocurcumin can form thermodynamically stable bonds with this receptor, with free enthalpy values of -6.4 Kcal/mol,; -6.1 Kcal/mol,; -6.1 Kcal/mol, ; -5.9 Kcal/mol, -5.9 Kcal/mol, -5.7 Kcal/mol,, -5.6 Kcal/mol, -5.5 Kcal/mol respectively, compared to the reference molecules analyzed (aspirin : -4.5 Kcal/mol and Ibuprofen: -5.4 Kcal/mol). These results show that metabolites resulting from the degradation of curcumin in the body can also form stable complexes with Cox-2.

In addition, the majority of the ligands mentioned above formed stable complexes with both cyclooxygenases 1 and 2; although the bonds formed by bisdemethoxycurcumin were very stable with free enthalpies of interaction of -8.8 Kcal/mol for the complex of this ligand with Cox-1 and -6.1 Kcal/mol for the complex of this ligand with Cox-2. In addition, curcumin, cyclocurcumin and demethoxycurcumin also formed highly stable complexes with the two enzymes (Cox-1 and Cox-2). As for the metabolites produced by the degradation of curcumin in the body, in silico screening showed that curcumin sulphate can form a very stable complex compared with those of other metabolites. The metabolites produced by the degradation of curcumin in the body are presented as inactive compounds [6, 33, 67] but the findings of the current research show that they can interact with cyclooxygenases and may have anti-inflammatory potential.

4.1.2. Types of interactions and amino acids involved in the formation of ligand complexes with Cox-1 or Cox-2

Most of the ligands analyzed can interact with amino acid residues found in the active site of the biological receptors studied (Cox-1 or Cox-2) as shown in table 2. For Cox-1, the screening revealed that the reference anti-inflammatory agents could interact with a maximum of 16 amino acids in the active site, including: Ser A:154; Pro A:40; Cys A:41; Gly A:45; Gln A:42; His A:43; Gln A: 44; Arg A:469; Leu A:152; Glu A:465; Cys A:47; Cys A:36; Gln A:461; Pro A:153; Tyr A:39; Pro A:156; 13 of these residues interacted with the two reference molecules while three residues (Ser A:154 and Cys A:36, Pro A 40) interacted essentially only with ibuprofen. En outre, la curcumine, ses dérivés ou métabolites ont interagi avec 8 à 13 acides aminés de la cavité du site actif de Cox-1. Curcumin, demethoxycurcumin and also curcumin sulphate, interacted with 13 amino acid residues. Bisdemethoxycurcumin and glucuronocurcumin interacted with 12 amino acids, while hexahydrocurcumin interacted with 11; cyclocurcumin (10) and dihydrocurcumin (10) interacted with 10 amino acids. However, tetrahydrocurcumin and hexahydrocurcuminol interacted with fewer amino acids in the cox-1 active site, 9 and 8 amino acids respectively.

With regard to the interaction of curcumin, its derivatives and metabolites with cox-2, Table 2 shows that the reference molecules ibuprofen and aspirin interacted with 8 amino acids of the active site, particularly Leu A:93; Ile A:92; Val A:89; Trp A:100; Ile A:112; Tyr A:115; Leu A:111 and Val A:116. The last residue only interacted with aspirin. Curcumin, its derivatives and metabolites interacted with 1 to 8 residues of the cox-1 active site. Curcumin, cyclocurcumin, demethoxycurcumin, curcumin sulphate and tetrahydrocurcumin interacted with 8 amino acid residues of the cox-2 active site, while bisdemethoxycurcumin and dihydrocurcumin interacted with 7 amino acids of the cox-2 active site; hexahydrocurcuminol interacted with 6 amino acids of cox-2. Glucuronocurcumin reacted with only 1 amino acid.

The ligands analyzed inhibit the action of Cox-1 more effectively than cox-2 as analyzed in tables 1 & 2. This is because they interact more with the amino acid residues of the cox-1 active site cavity and showed a high docking score when binding with Cox-1. For each ligand analyzed, the free enthalpy of complexation was lower for targeting with Cox-1 than Cox-2. This indicates that the ligands formed stable complexes with Cox-1 rather than Cox-2.

It is known that the interaction between a therapeutic target (receptor) and an active molecule (ligand or substrate) constitutes a crucial phase in the therapeutic action of the latter [68]. The fact that most of the ligands analyzed interact strongly with Cox-1 and/or Cox-2 catalytic sites predicts that these compounds would have anti-inflammatory properties.

Furthermore, according to Selvam et al. [69] and Jourdan [70], valine 116, is among the amino acid residues found in the Cox-2 catalytic site. The fact that the majority of the ligands studied (bisdemethoxycurcumin, curcumin, cyclocurcumin, demethoxycurcumin, dihydrocurcumin, hexahydroxycurcumin, hexahydroxycurcuminol, curcumin sulphate and tetrahydrocurcumin) interact with Val 116, predicts that these ligands can bind to the Cox-2 active site cavity and may compete with arachidonic acid, which is its natural substrate. Jourdan [70] also reported that C. longa compounds reduce phosphorylation of cytosolic phospholipase A2, which in turn interferes with prostanglandin anabolism.

This study enabled us to demonstrate in silico the action of curcuminoids and also curcumin metabolites against Cox-1 and Cox-2, which are involved in the inflammation process. The findings of in silico screening revealed that curcuminoids, metabolites produced by the metabolization of curcumin in the body can also interact with Cox by binding to their catalytic sites. These metabolites could potentially have anti-inflammatory activity by competing with the natural substrate of Cox.

Furthermore, curcumin and its derivatives can all form stable complexes with cyclooxygenases 1 and 2 by binding to their catalytic sites. The addition of their free energy of complexation shows that curcuminoids can act synergistically against Cox 1 and 2.

BDMC : Bisdemethoxycurcumin

Cox 1 : Cyclooxygenase 1

Cox 2 : Cyclooxygenase 2

DMC : Demethoxycurcumin

LOX : Lipoxygenase

NF : Nuclear factor

THC : Tetrahydrocurcumin

TNF :Tumour necrosis factor

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and material

The data supporting the findings of this study can be obtained from the corresponding authors upon reasonable request.

Competing interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Funding

This study was funded by the Service de Coopération et d'Action Culturelle of the French Embassy to one of the authors, Mbadiko Mutunda Clément (grant number FSPI 23-24). This helped to the completion of this work. The funder did not influence the findings of this study.

Author’s contributions

CM: Investigation, Data curation & analysis, Interpretation of data, Original Draft preparation, KNN: Data curation & analysis, Interpretation of data, Revision of draft, GB: Data curation, Original draft preparation, AM: Data analysis, Design of all the ligands used, Revision of draft, JK: Data analysis, JPN: Interpretation of data, Original draft preparation, NN, KP: Investigation, Revision of draft, TM: Study conception, Supervision , PM: Study conception, Data analysis, Supervision, Funding acquisition. All authors read and approved the final version of this manuscript.

Acknowledgements

The authors would like to thank the Service de Coopération et d'Action Culturelle of the French Embassy for the grant awarded to one of the authors, Mbadiko Mutunda Clément (grant number FSPI 23-24), who greatly contributed to the completion of this work.

Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this paper

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The authors declare no competing interests.

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In silico analysis of the anti-inflammatory activity of curcuminoids and/or curcumin metabolites on Cox-1 and Cox-2

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Abstract

Background

Results

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1. Introduction

2. Methods

2.1. Activity against sickle cell disease in silico

2.1.1. Receptor preparation

2.1.2. Preparation of ligands

2.2. Molecular docking

3. Results

3.1. In silico anti-inflammatory activity

4. Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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