Next Article in Journal
Complex of Barley Leaf Spots in Ukraine
Previous Article in Journal
Evaluation of the Environmental Performance of Stevia Glycoside Production Using Precision Agriculture and Green Processing Techniques
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Chemistry Proceedings
Volume 8
Issue 1
10.3390/ecsoc-25-11766
chemproc-logo
Submit to this Journal
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Proceeding Paper

Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor †

by
Oscar Collado García
1,2,3,*,
Hans De Winter
2,
Paul Cos
3,
Maria João Matos
4,5,
Eugenio Uriarte
4,6,
Gabriel Llaurado Maury
7,
Jorrit De Waele
8,
Glay Chinea Santiago
9 and
Enrique Molina
1,2,3
1
Department of Chemistry, Faculty of Applied Sciences, University of Camagüey, Camagüey 74650, Cuba
2
Laboratory of Medicinal Chemistry, University of Antwerp, BE-2610 Antwerp, Belgium
3
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, BE-2610 Antwerp, Belgium
4
Department of Organic Chemistry, Faculty of Pharmacy, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain
5
CIQUP/Department of Chemistry and Biochemistry, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
6
Institute of Applied Chemical Sciences, Autonomous University of Chile, Santiago de Chile 7500912, Chile
7
Center for Industrial Biotechnology (CEBI), Universidad de Oriente, Santiago de Cuba 90500, Cuba
8
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, BE-2610 Antwerp, Belgium
9
Bioinformatics Group, Center for Genetic Engineering and Biotechnology, Havana 10600, Cuba
*
Author to whom correspondence should be addressed.
†
Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2021; Available online: https://ecsoc-25.sciforum.net/.
Chem. Proc. 2022, 8(1), 77; https://doi.org/10.3390/ecsoc-25-11766
Published: 14 November 2021
(This article belongs to the Proceedings of The 25th International Electronic Conference on Synthetic Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
Anti-HIF flavonoids have been described for their antitumor activity by interfering with a presumed antioxidant mechanism through direct and indirect ways of overexpression of the hypoxia inducible factor (HIF-1α). The aryl hydrocarbon receptor (AhR) is a protein homologous to HIF-1α and is overexpressed in smoking patients suffering from lung and breast cancer. The interaction of thirteen flavonoids with the AhR has been evaluated by molecular docking. The AhR:ARNT model obtained by SwissModel has been used for docking with the MOE 2019.01 program, as well as several servers for the determination of protein–protein interactions and alanine mutations. Different interaction sites were identified for blocking the AhR: functional ARNT, the interface between the bHLH and PAS-A domains, being important. The blocking capacity to AhR:ARNT proved to be between 50 and 60% for flavonoids 4′,7-dihydroxy-flavone, fisetin, luteolin, 5-hydroxy-2-(4′-hydroxy)-7-methoxy-flavonone, flavone, apigenin, galangin and 7-hydroxy-5-methoxy-flavonone. None of the flavonoids evaluated interact with the PAS-B domain (AhR active site). All the studied flavonoids interact with AhR, except flavone, and with ARNT except the compounds 3,7-dihydroxy-flavone and kaempferol. The best flavonoid for blocking the formation of the AhR:ARNT heterodimer proved to be fisetin, which is found in food sources such as strawberries, apples and grapes, and has shown the ability to reduce pro-cancer inflammatory markers in colorectal cancer patients and lung cancer.

1. Introduction

The aryl hydrocarbon receptor (AHR), also known as the dioxin receptor, is traditionally defined as a ligand-dependent transcription factor involved in biotransformation and carcinogenic/teratogenic effects of environmental toxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [1]. The AHR is a basic transcription factor that contains helix-loop-helix (bHLH) and Per-Arnt-Sim (PAS). It is present in numerous animal species, including humans, and activates gene expression in a ligand-dependent manner. Ligand binding in the PAS-B domain of AHR leads to nuclear translocation and heterodimerization with the AHR nuclear translocator protein (ARNT). This AHR:ARNT heterodimer binds to DNA sequences, called xenobiotic-responsive elements or dioxin responsive elements (XRE or DRE), that are distributed in the enhancer regions of dioxin-responsive genes and regulate the expression of target genes. The binding of the ligand to AHR occurs on the PAS-B domain. AHR:ARNT dimerization involves interactions between its bHLH and PAS domains, and DNA binding occurs primarily through its basic domains. AHR is overexpressed in patients with lung and colorectal cancer. The search for new antitumor compounds is an important research area to improve effectiveness, increase survival, as well as to decrease multidrug resistance, adverse reactions and mortality in these patients [2,3,4,5,6,7].
Polyphenols are natural plant compounds and are the most abundant antioxidants in the human diet [8]. In general, antioxidants are defined as substances capable of reducing and preventing the oxidation of a substrate (proteins, lipids, carbohydrates and DNA) at low concentrations, and are present in vegetables, fruits and cereals that are usually consumed as natural diets, because they are safe and provide a large number of health benefits [9,10]. Polyphenols, which are composed of aromatic rings with one or more hydroxyl groups and are grouped in this classification more than 8000 compounds. Polyphenols are subdivided into several groups and the most important polyphenol subclasses are phenolic acids, flavonoids, stilbenes and lignans [10].
Taking this into account and considering that flavonoid compounds are well known and have characteristics that have made them attractive for cancer research, we proceeded to determine by molecular docking the interaction of flavonoids with the receptor AHR to block the formation of the functional heterodimer.

2. Materials and Methods

Molecular docking: A database created of flavonoids was used for modeling, thus a model obtained by SwissModel Web Server of the AHR receptor and its heterodimer complex with ARNT using as the crystal structure of ARNT (PDB: 4zp4) and the AHR sequence. For molecular modeling visualization, presentation of complexes, poses and interactions, the MOE 2019.01 program was used. The server programs Cocomaps (bioCOmplexes Contact MAPS) was used for the determination of atomic contacts between protein interfaces of the AHR:ARNT [11]. Important amino acid residues for protein-protein interaction as well as flexibility of alanine mutations were determined with Robetta and Rosetta Backrub web servers [12,13].
A positive control was used as proof of concept for the antiproliferative activity in the lung cancer cell line (A549) and for the identification of a new binding site: 5,7-diacetoxy-3-phenylcoumarin.

3. Results and Discussion

The activation of AHR is associated with an increase of the oxidative metabolism, and consequently, with the formation of, for instance, reactive oxygen species. Hence, this interaction with DNA in XRE is highly associated with the onset of further toxicity events that include carcinogenicity due to a prolonged AHR activity, development and reproductive toxicity, and immunological deterioration, known as dioxin toxicity effects [1,6,7,14,15,16,17,18,19,20,21,22].
The architecture of the interaction of AHR with ARNT to form the functional AHR:ARNT heterodimer is presented in Figure 1. Dioxins and dioxin-like substances can cause cancer and the high AHR conservation level shows the binding site of the ligand in the internal cavity at AHR PAS-B domain [1,14,23,24].
The protein-protein interactions (PPIs) are an integral part of most biological functions. Compared to targeting to the active site, inhibition of PPI suffers from the particular problem of more exposed and less defined binding sites, and this poses significant experimental challenges for the development of PPI inhibitors, although the discovery and subsequent refinement of the PPI inhibitors with strong affinity have proven to be a challenging pursuit, although not impossible [25,26,27].
The flavonoids studied in the molecular modeling study at the surface level of the AHR bind to contact interfaces at the level of the bHLH, PAS-A domains and the bHLH/PAS-A (yellow color circle) (Figure 2 and Figure 3). Therefore, these compounds can present a certain antagonistic behavior due to interactions at the level of the contact surfaces to block PPIs between AHR and ARNT (yellow color circle), is identified as a new binding site where flavonoids can interfere with the formation of the functional AHR:ARNT heterodimer, according to its modeling with Swiss Model [24].
In the case of ARNT, the flavonoids essentially bind to the surface interfaces of the bHLH and PAS-A domains, in the latter the α-helix is noteworthy, where the Asp161, Leu164, Lys165, Ile168, Leu176 and Tyr188 residues are found, that are visually identified as essential for the interaction between the PAS-A (AHR)/PAS-A (ARNT) domains (Figure 4).
The compounds presented in Table 1 and Table 2, as well as compounds 18 and 19 (Figure 5), have different probabilities of blocking the formation of the AHR:ARNT heterodimer, with compounds 1–6, 15–16 being those with a blocking percentage ≥ 50%, so they are considered the best, although all the modeled compounds in some way can interfere in the formation of the heterodimer under study by interfering with the PPI. It is important to note that flavonoids are one of the major classes of dietary-derived AHR ligands. The flavonoids are a large class of polyphenolic secondary metabolites that are widely distributed in fruits and vegetables. Quercetin, taxifolin, and robinetin are reported to be able to activate the AHR, while luteolin act as AHR antagonists [28,29,30,31,32]. Other polyphenols are reported to have activity to block PPI at the AHR and ARNT level [24].

3.1. Active Flavonoids with a Probability of Blockage Higher Than 50%

Compound 1 (Figure 6) can interact with the AHR and the ARNT to block the interactions between both proteins. As can be seen in the three poses represented in the environment of the interactions with the amino acid residues, this compound interacts through hydrogen bonds with the Lys79 residue and through π-π interactions with the Phe260 residue, also through hydrophobic interactions this compound is probably capable of interfering by causing steric impediments and affecting the atomic contacts established between the following residues at the level of the bHLH/PAS-A interface and the PAS-A domain of AHR. Phenylalanine Phe260 is reported by Corrada et al. (2017) as an important residue at the PAS-A domain level for interaction with ARNT [6]. In the case of interactions with ARNT, compound 1 interacts through hydrogen bonds with residues Thr110, Ser120, where only serine has atomic contacts (≤6Å) with AHR residues, so it can affect these interactions. In the case of the threonine residue (Thr110), it is not an important residue nor does it present atomic contacts with its partner (ARNT) at a distance ≤ 6Å. The amino acid residues between 88 and 128 of ARNT are important for DNA binding to develop its activity in combination with its partner (UniProt P53762) [33].
Similarly to compound 1, compound 2 (fisetin) also interacts with the two proteins under study (putative target), with a greater probability of direct interaction with ARNT compared to AHR (Figure 7). Interactions at the AHR level are established at the bHLH/PAS-A interface of the AHR. The binding by hydrogen bonds to the Arg236 and Gly250 residues enable the interaction and interference with amino acid residues in that region and that present some atomic contacts (≤6Å) with the amino acids of the ARNT partner. In this specific case, the identified amino acid residues are listed below: Val73, Leu76, Arg77, Phe81, Phe82, Ser88, Arg236, Lys238 and Phe260. It is important to note that in this region the amino acid Lys238 is reported to be important for the binding of the AHR:ARNT heterodimer to the DRE box to develop target gene activation activity (UniProt P30561) [1,24,33]. The interaction of compound 2 with ARNT is also important, and like compound C1, it interacts at the level of the bHLH domain with bonds to the two threonine and serine residues highlighted above, but also establishing a bond of this type with the Ser228 residue that is not a residue with atomic contacts with the AHR, but in a region where there are amino acid residues capable of interacting with the AHR (e.g., pose 5, Arg261, Ile312, Lys313, Ala314 and Phe335). Compound 2 can cause interference through hydrophobic interactions at the level of these bHLH and PAS-A domains at ARNT, in the latter by binding to the α-helix where residues Leu164, Lys165, Ile168, Leu176 and Tyr188 are found, all with atomic contacts (≤6Å) with AHR according to the analyzed model. This is in correspondence with those reported in UniProt, which reports that the surface region between residues 167 and 171 of AHR is essential for the dimerization process of ARNT with AHR (UniProt P53762) [33].
Compound 3 (3-methylleuteoline) preferentially interacts with AHR than with ARNT (Figure 8). At the AHR level, this compound interacts with the surface interface between the bHLH and PAS-A domains (bHLH/PAS-A). This compound binds via hydrogen bonds to amino acids Phe55 and Lys79 that establish atomic contacts (≤6Å) with the ARNT partner, and also binds to Asp249, but this is not an important residue for the formation of the heterodimer. In the surface region of interaction of compound 3, the following amino acids present some type of atomic contact (≤6Å) with ARNT, and are listed below: Pro54, Phe55, Leu71, Ser74, Try75, Arg77, Ala78, Lys79, Phe81, Phe82, Val124, Leu125, Val126, Phe134, Tyr135, Ser138, Gln148, Ile152, Phe260, Ala261 and Ile262. It should be noted that in this surface region are the amino acids Pro54 and Phe55 that are described in UniProt as important, the amino acid sequence 37 to 65 of the peptide chain of AHR as important for DNA binding, Val124 and Phe260 is required for the integrity of the AHR:ARNT, Phe134 and Ile152 are important for the activity of the AHR (UniProt P30561) [33]. By also binding the compound 3 to the ARNT, it can therefore block the formation of the functional heterodimer, in this case at the interface that encompasses the PAS-A domains and the surface between the PAS-A and PAS-B domains (PAS-A/PAS-B), so through a hydrogen bond with the amino acid Lys334 and hydrophobic interactions it can cause steric impediments for the formation of the heterodimer and thus interfere with the atomic contacts (≤6Å) that can be established at the level of some of the ARNT amino acids listed below: Asp173, Ala185, Val 187, Phe205, Val305, Trp315, Lys334, Phe335, Leu343, Gln344 and Tre346. It is important to highlight that Val 305 of this group is reported as important to guarantee the stability of AHR:ARNT (UniProt P53762) [33].
Compound 4 (Apigenin, Figure 9) and presents hydrogen bond bonds with the AHR and with ARNT. At the AHR level, this compound interacts at the level of the surface that forms between the bHLH and PAS-A (bHLH/PAS-A) domains, in the environment of the same amino acids listed for the case of compound C3, except for the following: Phe55, Arg77, Ser138, Gln148, Ala261 and Ile262 and including Ser88 with which it establishes a hydrogen bond and which is a residue that establishes atomic contacts (≤6Å) and Lys238 whose importance has already been mentioned. In the case of interactions with ARNT, compound C4 interacts in a similar way to compound 1.

3.2. Active Flavonones with a Probability of Blockage Higher Than 50%

Compound 5 (flavone) exhibits a preferential interaction with ARNT over AHR, but with a 50% probability of blocking the formation of the AHR:ARNT heterodimer (Figure 10). The binding of compound 5 to AHR is established by interaction through hydrogen bonding with Ser88 in a region where other amino acids also establish atomic contacts (≤6Å, Thr89, Arg236, Lys238 and Phe260), standing out the same considerations as those mentioned above for Lys238 and Phe260. The level of ARNT, compound 5 binds in the bHLH domain to Thr106, Thr110, Ser113 and Lys125, which do not have atomic contacts with the amino acids of the AHR, but it does bind to the Leu164, which does have contacts with AHR. However, they can interfere with some of the other amino acids that do interact with the AHR (e.g., Ile109, Asp114, Asp127 and Lys128). At the level of the α-helix in the PAS-A domain of ARNT where the Leu164 found (Lys165, Ile168, Leu176 and Tyr188), compound 5 can interfere with this surface by binding to this residue, which is important for establishing interactions with the AHR.
Compound 6 (galagin) exhibits a preferential binding behavior for ARNT comparing to AHR; However, based on the structural analysis criteria, it is possible that it interferes by 50% in the formation of the AHR:ARNT heterodimer (Figure 11). Like the previous compounds, this compound binds to the bHLH/PAS-A surface interface through interactions that are established with the following amino acid residues that have atomic contacts (≤6Å) with ARNT and include Lys79, Ser88 and Phe260. The importance of its interaction and bind with Phe260 is also highlighted, which is in correspondence with that reported by Corrada et al. 2017 and UniProt P30561 [6,33], as well as the presence on that surface of Pro54, that is present in the region that is important for the binding of AHR to DNA between residues 37 and 65, the Val124 that is reported as necessary to guarantee the integrity of the AHR, the Phe134 whose mutation by aspartic acid causes the decrease in the activity of the AHR, and Lys238 which mutation by aspartic acid would reduce the binding affinity of the heterodimer to the DRE (UniProt P30561) [33]. Compound 6 binds in ARNT to amino acids Thr106, Thr110, Ser113, Pro126, Asp114 and Asp127, where the first four do not have atomic contacts (≤6Å) with AHR, but Asp114 and Asp127 do. It should also be noted that somehow, compound 6 can interfere with the interactions established by the following ARNT amino acids that have already been previously mentioned (Ile109 and Ser120).
The compound 15 [5-hydroxy-2-(4’-hydroxy)-7-methoxy-flavonone, Figure 12] also interacts with AHR and ARNT, with AHR it binds through the amino acids Arg78 and Lys79 that present atomic contacts (≤6Å). In this surface environment, there are amino acids that in various ways contribute to the formation and stability of the AHR:ARNT heterodimer, such as Phe260 and Leu240, which are reported to be also important for the affinity of the heterodimer to the DRE (UniProt P3056) [33]. At the level of the interfaces that are formed in bHLH, PAS-A, and PAS-A/PAS-B at ARNT, compound 15 interacts through hydrophobic interactions, highlighting the interaction that occurs in the α-helix where the residues are found Asp161, Leu164, Lys165, Ile168, Leu176 and Ile340, all with atomic contacts (≤6Å) with AHR.
Compound 16 (7-hydroxy-5-methoxy-flavonone, Figure 13) has a preferential binding percentage for AHR to ARNT. Due to hydrophobic interactions, it binds to the bHLH domain where Ile109, Asp114, Asp127 and Lys128 have atomic contacts (≤6Å) with AHR. With the AHR, compound 16 only binds to two arginine residues (Arg217 and Arg236), Arg217 does not have atomic contacts with ARNT and Arg236 does, as already mentioned for compound 5. As previously described, the binding of this compound on the surface of AHR developed in the bHLH/PAS-A interface, and in the PAS-A/PAS-B of AHR (Lys238 and Phe260), are important residues for the formation of the heterodimer.
In summary, the compounds that present the highest percentages of probability to modulate the blockade of the formation of the functional AHR:ARNT heterodimer due to their binding to important interfaces according to the results of the AHR molecular docking are compounds 3, 1, 15 and 16, while for ARNT are compounds 2, 5, 1, 4, 6 and 15. From all the studied flavonoids, compounds 1 and 15 have equivalent potential to modulate the blockade of this heterodimer. The best compound to bind to AHR is compound 3, and best compounds to bind ARNT it is compounds 2 and 5.

3.3. Proof of Concept

In the A549 lung cancer cell line in which the AHR is overexpressed [34,35,36,37], compound 20 presented a percentage of activity of 40% in the selected modeling conditions. This compound (5,7-diacetoxy-3-phenylcoumarin) proved to bind to the bHLH/PAS-A interface (Figure 14), interfering through possible steric impediments, with the formation of the AHR:ARNT heterodimer by binding to AHR through hydrophobic interactions. The coumarin ring has the ability to establish different types of non-covalent interactions including hydrophobic, π-π and electrostatic forces, as well as hydrogen bonds, van der Waals forces, among others, with other active molecules and the active site on different targets of living organisms [38].The structure of the coumarin nucleus allows the formation of π-π type interactions in the rings with residues of a hydrophobic nature in the environment of the protein surface (hydrophobic patches), in particular with Phe260, Tyr75 and Tyr135.
The proof of concept carried out with coumarin 20 comparing to the studied flavonoids obeys more than a structure-activity relationship, and is directed towards a structural identification at the level of the AHR receptor as a possible new surface binding site (site allosteric) for the modulation of the activity of this receptor in the formation of the functional AHR:ARNT heterodimer, since the antiproliferative effect of flavonoids is fundamentally associated with their activity as an antioxidant [9,10,39]. Compound 20 decreased the proliferation of A549 lung cancer cells below 50% (Table 3). Therefore, it is expected that flavonoids that also bind to this interface bHLH/PAS-A of AHR, may modulate the antiproliferative activity via another mechanism of action. The properties of the surfaces of the domains and protein-protein interfaces can be predicted by appropriate docking methods or by template-based models. Therefore, these models only represent the starting point to analyze the processes by which ligands can affect AHR activation, dimerization, and transformation in their functional form and DNA binding [40]. Therefore, in a preliminary way, all this structural information can be used for the identification of new molecular entities capable of interfering in the activity of the AHR.

4. Conclusions

Eight flavonoids with potential activity blocking the AHR:ARNT heterodimer have been identified by molecular docking, with probability percentages between 50 and 60%. The flavonoid interactions at the interface surfaces of the bHLH and PAS-A domains of AHR and ARNT have proved to occur mainly by hydrogen bonding and hydrophobic interactions, without binding to the PAS-B domain of AHR. A new surface binding site is proposed at the level of the bHLH/PAS-A interface as the most likely site to which 74% of the studied flavonoids bind to the interfere with the formation of the complex. Glycosylated flavonoids showed AHR:ARNT blocking percentages of lower than 50%. In the case of flavonones, the incorporation of a hydroxyl group in position R4′ proved to increase the activity by 30%. It is estimated that the flavonoids identified as active display antiproliferative activity in lung cancer cells (A549) due to the structural similarity with the nucleus of the evaluated coumarin, which presented a blocking percentage of the AHR:ARNT of 40%, binding to the same site of the AHR surface interface. As proof of concept, the synthetic 5,7-diacetoxy-3-phenylcoumarin have been studied. This compound proved to decrease the proliferation of A549 lung cancer cells below 50%.

Supplementary Materials

The poster presentation can be downloaded at: https://www.mdpi.com/article/10.3390/ecsoc-25-11766/s1.

Author Contributions

Conceptualization, O.C.G., H.D.W., E.M., P.C., G.C.S. and E.U.; methodology, O.C.G., M.J.M., J.D.W. and G.L.M.; software, G.L.M., J.D.W. and G.C.S.; validation, O.C.G., J.D.W. and H.D.W.; formal analysis, G.L.M. and J.D.W.; investigation, O.C.G., P.C., E.M., G.C.S. and M.J.M.; resources, E.U., E.M. and P.C.; data curation, O.C.G., H.D.W., P.C., G.L.M., G.C.S., E.U. and M.J.M.; writing—original draft preparation, O.C.G., P.C., H.D.W. and G.L.M.; writing—review and editing, P.C., E.M., E.U. and M.J.M.; visualization, G.L.M., J.D.W. and G.C.S.; supervision, H.D.W., P.C., E.M. and E.U.; project administration, P.C. and E.M.; funding acquisition, P.C. and E.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research has been partially funded by the Belgian Development Cooperation, through the VLIR-UOS (Council of Flemish Universities), through the TEAM Project with reference CU2017TEA433A102. This research was partially supported by Fundação para a Ciência e Tecnologia (FCT, PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Collado García, O.; Álvarez Gil, M.; Martínez Sáez, S. Aryl Hydrocarbon Receptor Agonists as Contaminants in the Feed for Production Animals. J. An. Prod. 2022, 34. Available online: https://revistas.reduc.edu.cu/index.php/rpa/article/view/e4044 (accessed on 14 October 2021).
  2. Salzano, M.; Marabotti, A.; Milanesi, L.; Facchiano, A. Human aryl-hydrocarbon receptor and its interaction with dioxin and physiological ligands investigated by molecular modelling and docking simulations. Biochem. Biophys. Res. Commun. 2011, 413, 176–181, Erratum in: Biochem. Biophys. Res. Commun. 2012, 418, 852. [Google Scholar] [CrossRef] [PubMed]
  3. Denison, M.S.; Soshilov, A.A.; He, G.; DeGroot, D.E.; Zhao, B. Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 2011, 124, 1–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Wu, D.; Potluri, N.; Kim, Y.; Rastinejad, F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Mol. Cell. Biol. 2013, 33, 4346–4356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Corrada, D.; Soshilov, A.A.; Denison, M.S.; Bonati, L. Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation. PLoS Comput. Biol. 2016, 12, e1004981. [Google Scholar] [CrossRef] [PubMed]
  6. Corrada, D.; Denison, M.S.; Bonati, L. Structural modeling of the AhR:ARNT complex in the bHLH-PASA-PASB region elucidates the key determinants of dimerization. Mol. Biosyst. 2017, 13, 981–990. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Goya-Jorge, E.; Jorge Rodríguez, M.E.; Veitía, M.S.-I.; Giner, R.M. Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor. Molecules 2021, 26, 2315. [Google Scholar] [CrossRef]
  8. Ray, S.K.; Mukherjee, S. Evolving Interplay Between Dietary Polyphenols and Gut Microbiota-An Emerging Importance in Healthcare. Front. Nutr. 2021, 8, 634944. [Google Scholar] [CrossRef]
  9. Guardado, E.; Molina, E.; João, M.M.; Uriarte, E. Antioxidant and Pro-Oxidant Effects of Polyphenolic Compounds and Structure-Activity Relationship Evidence. Nutr. Well-Being Health 2012, 2, 23–48. [Google Scholar] [CrossRef] [Green Version]
  10. Llauradó Maury, G.; Méndez Rodríguez, D.; Hendrix, S.; Escalona Arranz, J.C.; Fung Boix, Y.; Pacheco, A.O.; García Díaz, J.; Morris-Quevedo, H.J.; Ferrer Dubois, A.; Aleman, E.I.; et al. Antioxidants in Plants: A Valorization Potential Emphasizing the Need for the Conservation of Plant Biodiversity in Cuba. Antioxidants 2020, 9, 1048. [Google Scholar] [CrossRef]
  11. Vangone, A.; Spinelli, R.; Scarano, V.; Cavallo, L.; Oliva, R. COCOMAPS: A web application to analyze and visualize contacts at the interface of biomolecular complexes. Bioinformatics 2011, 27, 2915–2916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Kortemme, T.; Baker, D. A simple physical model for binding energy hot spots in protein-protein complexes. Proc. Natl. Acad. Sci. USA 2002, 99, 14116–14121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Kortemme, T.; Kim, D.E.; Baker, D. Computational alanine scanning of protein-protein interfaces. Sci STKE 2004, 2004, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Szöllősi, D.; Erdei, Á.; Gyimesi, G.; Magyar, C.; Hegedűs, T. Access path to the ligand binding pocket may play a role in xenobiotics selection by AhR. PLoS ONE 2016, 11, e0146066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Schulte, K.W.; Green, E.; Wilz, A.; Platten, M.; Daumke, O. Structural basis for aryl hydrocarbon receptor-mediated gene activation. Structure 2017, 25, 1025–1033. [Google Scholar] [CrossRef] [Green Version]
  16. Tuomisto, J.; Airaksinen, R.; Pekkanen, J.; Tukiainen, E.; Kiviranta, H.; Tuomisto, J.T. Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies. Toxicol. Lett. 2017, 270, 8–11. [Google Scholar] [CrossRef] [Green Version]
  17. Hattori, Y.; Takeda, T.; Nakamura, A.; Nishida, K.; Shioji, Y.; Fukumitsu, H.; Yamada, H.; Ishii, Y. The aryl hydrocarbon receptor is indispensable for dioxin-induced defects in sexually-dimorphic behaviors due to the reduction in fetal steroidogenesis of the pituitary-gonadal axis in rats. Biochem. Pharmacol. 2018, 154, 213–221. [Google Scholar] [CrossRef]
  18. Danjou, A.M.; Coudon, T.; Praud, D.; Lévêque, É.; Faure, É.; Salizzoni, P.; Le Romancer, M.; Severi, G.; Mancini, F.R.; Leffondré, K.; et al. Long-term airborne dioxin exposure and breast cancer risk in a case-control study nested within the French E3N prospective cohort. Environ. Int. 2019, 124, 236–248. [Google Scholar] [CrossRef]
  19. Mengoni, M.; Braun, A.D.; Gaffal, E.; Tüting, T. The aryl hydrocarbon receptor promotes inflammation-induced dedifferentiation and systemic metastatic spread of melanoma cells. Int. J. Cancer 2020, 147, 2902–2913. [Google Scholar] [CrossRef]
  20. Sadik, A.; Patterson, L.F.; Öztürk, S.; Mohapatra, S.R.; Panitz, V.; Secker, P.F.; Pfänder, P.; Loth, S.; Salem, H.; Prentzell, M.T.; et al. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell 2020, 182, 1252–1270. [Google Scholar] [CrossRef]
  21. Haidar, R.; Henkler, F.; Kugler, J.; Rosin, A.; Genkinger, D.; Laux, P.; Luch, A. The role of DNA-binding and ARNT dimerization on the nucleo-cytoplasmic translocation of the aryl hydrocarbon receptor. Sci. Rep. 2021, 11, 18194. [Google Scholar] [CrossRef] [PubMed]
  22. Zhai, Y.; Amadou, A.; Mercier, C.; Praud, D.; Faure, E.; Iwaz, J.; Severi, G.; Mancini, F.R.; Coudon, T.; Fervers, B.; et al. The impact of left truncation of exposure in environmental case–control studies: Evidence from breast cancer risk associated with airborne dioxin. Eur. J. Epidemiol. 2022, 37, 79–93. [Google Scholar] [CrossRef] [PubMed]
  23. Panda, R.; Cleave, A.S.S.; Suresh, P.K. In silico predictive studies of mAHR congener binding using homology modelling and molecular docking. Toxicol. Ind. Health 2014, 30, 765–776. [Google Scholar] [CrossRef] [PubMed]
  24. Collado García, O.; Rodríguez Torrens, H.; Barreto Argilagos, G. The Role of Aryl Hydrocarbon Receptor-Microbiota Interactions in the Litter and Pre-Fattening Pigs’ Health. J. Anim. Prod. 2022, 34. Available online: https://revistas.reduc.edu.cu/index.php/rpa/article/view/e4156 (accessed on 14 October 2021).
  25. Valkov, E.; Sharpe, T.; Marsh, M.; Greive, S.; Hyvönen, M. Targeting Protein–Protein Interactions and Fragment-Based Drug Discovery. Top. Curr. Chem. 2012, 317, 145–179. [Google Scholar] [CrossRef]
  26. Corbi-Verge, C.; Kim, P.M. Motif mediated protein-protein interactions as drug targets. Cell. Commun. Signal. 2016, 14, 8. [Google Scholar] [CrossRef] [Green Version]
  27. van Dun, S.; Ottmann, C.; Milroy, L.G.; Brunsveld, L. Supramolecular Chemistry Targeting Proteins. J. Am. Chem. Soc. 2017, 139, 13960–13968. [Google Scholar] [CrossRef]
  28. Ashida, H.; Fukuda, I.; Yamashita, T.; Kanazawa, K. Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin. FEBS Lett. 2000, 476, 213–217. [Google Scholar] [CrossRef]
  29. Zhang, S.; Qin, C.; Safe, S.H. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: Effects of structure and cell context. Environ. Health Perspect 2003, 111, 1877–1882. [Google Scholar] [CrossRef]
  30. Jin, U.H.; Park, H.; Li, X.; Davidson, L.A.; Allred, C.; Patil, B.; Jayaprakasha, G.; Orr, A.A.; Mao, L.; Chapkin, R.S.; et al. Structure-Dependent Modulation of Aryl Hydrocarbon Receptor-Mediated Activities by Flavonoids. Toxicol. Sci. 2018, 164, 205–217. [Google Scholar] [CrossRef] [Green Version]
  31. Gasaly, N.; Riveros, K.; Gotteland, M. Fitoquímicos: Una nueva clase de prebióticos. Rev. Chil. Nutr. 2020, 47, 317–327. [Google Scholar] [CrossRef]
  32. Han, H.; Safe, S.; Jayaraman, A.; Chapkin, R.S. Diet-Host-Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis. Annu. Rev. Nutr. 2021, 41, 455–478. [Google Scholar] [CrossRef] [PubMed]
  33. UniProt Consortium. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res. 2021, 49, D480–D489. [Google Scholar] [CrossRef] [PubMed]
  34. Edgell, C.J.; McDonald, C.C.; Graham, J.B. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc. Natl. Acad. Sci. USA 1983, 80, 3734–3737. [Google Scholar] [CrossRef] [Green Version]
  35. Luo, C.; Zou, P.; Ji, G.; Gu, A.; Zhao, P.; Zhao, C. The aryl hydrocarbon receptor (AhR) 1661G>A polymorphism in human cancer: A meta-analysis. Gene 2013, 513, 225–230. [Google Scholar] [CrossRef]
  36. Kolluri, S.K.; Jin, U.H.; Safe, S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch. Toxicol. 2017, 91, 2497–2513. [Google Scholar] [CrossRef]
  37. Wang, Z.; Snyder, M.; Kenison, J.E.; Yang, K.; Lara, B.; Lydell, E.; Bennani, K.; Novikov, O.; Federico, A.; Monti, S.; et al. How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression. Int. J. Mol. Sci. 2020, 22, 387. [Google Scholar] [CrossRef]
  38. Matos, M.J. Cumarinas: Versatilidad estructural y aplicaciones en Química Farmacéutica. Ph.D. Thesis, Universidad de Santiago de Compostela, Santiago, Spain, 2013; p. 342. [Google Scholar]
  39. Park, H.; Jin, U.H.; Orr, A.A.; Echegaray, S.P.; Davidson, L.A.; Allred, C.D.; Chapkin, R.S.; Jayaraman, A.; Lee, K.; Tamamis, P.; et al. Isoflavones as Ah Receptor Agonists in Colon-Derived Cell Lines: Structure-Activity Relationships. Chem. Res. Toxicol. 2019, 32, 2353–2364. [Google Scholar] [CrossRef]
  40. Bonati, L.; Corrada, D.; Giani Tagliabue, S.; Motta, S. Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms. Curr. Opin. Toxicol. 2017, 2, 42–49. [Google Scholar] [CrossRef] [Green Version]
Chemproc 08 00077 g001 550
Figure 1. Structural architecture of the interaction of the monomers AHR and ARNT for the formation of the functional heterodimer AHR:ARNT modeled by SwissModel.
Figure 1. Structural architecture of the interaction of the monomers AHR and ARNT for the formation of the functional heterodimer AHR:ARNT modeled by SwissModel.
Chemproc 08 00077 g001
Chemproc 08 00077 g002 550
Figure 2. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of AHR modeled by SwissModel. bHLH-PAS-A (yellow color) and PAS-A (Red color).
Figure 2. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of AHR modeled by SwissModel. bHLH-PAS-A (yellow color) and PAS-A (Red color).
Chemproc 08 00077 g002
Chemproc 08 00077 g003 550
Figure 3. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of AHR modeled by SwissModel. bHLH-PAS-A (yellow) and PAS-A (red).
Figure 3. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of AHR modeled by SwissModel. bHLH-PAS-A (yellow) and PAS-A (red).
Chemproc 08 00077 g003
Chemproc 08 00077 g004 550
Figure 4. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of ARNT.
Figure 4. Interaction of flavonoids at the interface of the bHLH and PAS-A domains of ARNT.
Chemproc 08 00077 g004
Chemproc 08 00077 g005 550
Figure 5. Genistein and resveratrol, with the probability of blockage.
Figure 5. Genistein and resveratrol, with the probability of blockage.
Chemproc 08 00077 g005
Chemproc 08 00077 g006 550
Figure 6. Interaction network between monomeric proteins AHR, ARNT and the studied compound 1.
Figure 6. Interaction network between monomeric proteins AHR, ARNT and the studied compound 1.
Chemproc 08 00077 g006
Chemproc 08 00077 g007 550
Figure 7. Interaction network between monomeric proteins AHR, ARNT and the studied compound 2.
Figure 7. Interaction network between monomeric proteins AHR, ARNT and the studied compound 2.
Chemproc 08 00077 g007
Chemproc 08 00077 g008 550
Figure 8. Interaction network between monomeric proteins AHR, ARNT and the studied compound 3.
Figure 8. Interaction network between monomeric proteins AHR, ARNT and the studied compound 3.
Chemproc 08 00077 g008
Chemproc 08 00077 g009 550
Figure 9. Interaction network between monomeric protein AHR, ARNT and the studied compound 4.
Figure 9. Interaction network between monomeric protein AHR, ARNT and the studied compound 4.
Chemproc 08 00077 g009
Chemproc 08 00077 g010 550
Figure 10. Interaction network between monomeric proteins AHR, ARNT and the studied compound 5.
Figure 10. Interaction network between monomeric proteins AHR, ARNT and the studied compound 5.
Chemproc 08 00077 g010
Chemproc 08 00077 g011 550
Figure 11. Interaction network between monomeric protein AHR, ARNT and the studied compound 6.
Figure 11. Interaction network between monomeric protein AHR, ARNT and the studied compound 6.
Chemproc 08 00077 g011
Chemproc 08 00077 g012 550
Figure 12. Interaction network between monomeric protein AHR, ARNT and the studied compound 15.
Figure 12. Interaction network between monomeric protein AHR, ARNT and the studied compound 15.
Chemproc 08 00077 g012
Chemproc 08 00077 g013 550
Figure 13. Interaction network between monomeric protein AHR, ARNT and the studied compound 16.
Figure 13. Interaction network between monomeric protein AHR, ARNT and the studied compound 16.
Chemproc 08 00077 g013
Chemproc 08 00077 g014 550
Figure 14. Interaction network between monomeric protein AHR, ARNT and the studied compound 20.
Figure 14. Interaction network between monomeric protein AHR, ARNT and the studied compound 20.
Chemproc 08 00077 g014
Table
Table 1. Structures of flavones and flavonols active in blocking the formation of the functional heterodimer AHR:ARNT. Percentages of probability of the activity estimated by molecular docking.
Table 1. Structures of flavones and flavonols active in blocking the formation of the functional heterodimer AHR:ARNT. Percentages of probability of the activity estimated by molecular docking.
Chemproc 08 00077 i001
CompR3R5R6R7R8R3’R4´R5´AHR:ARNT
Prob (%)
1HHHOHHHOHH60
2OHHHOHHOHOHH60
3CH3OHHOHHOHOHH60
4HOHHOHHHOHH50
5HHHHHHHH50
6OHOHHOHHHHH50
7HOHHOCH3GluOHOHH40
8OHOHHOHHHOHH30
9HOHGluOCH3HHOHH30
10HHHOHHHOCH3H20
11OHOHHOHHOHOHOH20
12OHOHHOHHOHOHH20
13HOHGluOHHHOHH20
14OHHHOHHHHH10
Table
Table 2. Structure of active flavonones to block the formation of the functional heterodimer AHR: ARNT. Percentages of probability of the activity estimated by molecular docking.
Table 2. Structure of active flavonones to block the formation of the functional heterodimer AHR: ARNT. Percentages of probability of the activity estimated by molecular docking.
Chemproc 08 00077 i002
CompR5R7R4´AHR:ARNT
Prob (%)
15OHOCH3OH60
16OCH3OHH50
17OHOCH3H30
Table
Table 3. Antiproliferative activity of compound 20 on A549 lung cell line.
Table 3. Antiproliferative activity of compound 20 on A549 lung cell line.
Concentration
(µg/mL)		Determination 1Determination 2Mean% CV
814,45519,80417,1292208
1612,551995611,2541630
3214,01815,41314,716670
648487992192041102
128248627402613686
256−1702−1501−1602−885
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

García, O.C.; De Winter, H.; Cos, P.; Matos, M.J.; Uriarte, E.; Maury, G.L.; De Waele, J.; Santiago, G.C.; Molina, E. Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor. Chem. Proc. 2022, 8, 77. https://doi.org/10.3390/ecsoc-25-11766

AMA Style

García OC, De Winter H, Cos P, Matos MJ, Uriarte E, Maury GL, De Waele J, Santiago GC, Molina E. Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor. Chemistry Proceedings. 2022; 8(1):77. https://doi.org/10.3390/ecsoc-25-11766

Chicago/Turabian Style

García, Oscar Collado, Hans De Winter, Paul Cos, Maria João Matos, Eugenio Uriarte, Gabriel Llaurado Maury, Jorrit De Waele, Glay Chinea Santiago, and Enrique Molina. 2022. "Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor" Chemistry Proceedings 8, no. 1: 77. https://doi.org/10.3390/ecsoc-25-11766

Article Metrics

Back to TopTop