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Molecular docking investigation of cytotoxic phenanthrene derivatives
[Etude de l’amarrage moléculaire de dérivés phénanthréniques cytotoxiques]
Comptes Rendus. Chimie, Volume 23 (2020) no. 4-5, pp. 329-342.

Résumés

Our previous experimental work indicated that the presence of ester functionality in phenanthrene derivatives D-1 and D-2 leads to potent cytotoxicity against the Caco-2 cell line. The present work is based on th-is experimental result. First, we optimized the structures of the studied molecules using the density functional theory method. Then we performed a study about their potential biological importance by evaluating the binding mode and exploring their intermolecular interactions with appropriate proteins using molecular docking calculations. Consequently, we confirmed the results obtained from experimental studies. In particular, our study indicated that many promising proteins are able to bind and interact with the phenanthrene skeleton from the binding site. Methyl 8-methyl-9,10-phenanthrenequinone-3-carboxylate D-1 and methyl 8-methyldibenzo[a,c]phenazine-3-carboxylate D-2 displayed strong cytotoxicity. However, the best affinity is noted for B-Raf proto-oncogene serine/threonine-protein kinase (-9.8 Kcal/mol for molecule D-1 and -11.1 Kcal/mol for molecule D-2), which is higher than that of any other protein used. Especially, this protein is involved in sending signals inside cells that are involved in directing cell growth and is found to be a significant target in both types of studied cancers.

Nos travaux expérimentaux antérieurs ont indiqué que la présence de la fonction ester sur les dérivés phénanthréniques D-1 et D-2 a montré une cytotoxicité puissante contre la lignée cellulaire Caco-2. Dans ce présent travail, nous nous basons sur ces résultats obtenus expérimentalement. Tout d’abord, nous avons optimisé à l’aide de la méthode DFT les structures des molécules étudiées, puis nous avons mené l’étude de leur impo rtance biologique en évaluant le mode de liaison et en explorant leurs interactions intermoléculaires avec des protéines appropriées à l’aide des calculs d’amarrage moléculaire. Par conséquent, nous avons confirmé les résultats obtenus suite aux études expérimentales. En particulier, notre étude a indiqué que de nombreuses protéines prometteuses sont capables de se lier et d’interagir avec le squelette phénanthrénique à partir du site de liaison. Le 8-méthyl-9,10-phénanthrénequinone-3-carboxylate de méthyle D-1 et le 8-méthyldibenzo[a,c]phénazine-3-carboxylate de méthyle D-2 ont montré une forte cytotoxicité. La meilleure affinité est observée avec la protéine B-Raf proto-oncogène sérine/thréonine kinase (-9.8 Kcal/mol pour la molécule D-1 et -11.1 Kcal/mol pour la molécule D-2) qui est plus importante que celle de toute autre protéine utilisée. Ajoutons que, cette protéine est impliquée dans l’envoi de signaux à l’intérieur des cellules qui participent à la direction de la croissance ctextellulaire et se révèle être une cible significative dans les deux types de cancers étudiés.

Métadonnées
Reçu le :
Révisé le :
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DOI : 10.5802/crchim.27
Mots clés : Phenanthrene, Cytotoxicity, DFT calculations, Molecular modeling, Docking, Proteins
Habiba Guédouar 1 ; Hanane Zaki 2 ; Mohammed Bouachrine 3, 2 ; Faouzi Aloui 1

1 University of Monastir, Faculty of Sciences, Laboratory of Asymmetric Synthesis and Molecular Engineering of Materials for Organic Electronics (LR18ES19), Avenue of Environment, 5019 Monastir, Tunisia
2 Molecular and Computational Chemistry, Molecular Chemistry and Natural Substances Laboratory, Faculty of Sciences, University Moulay Ismail of Meknes, BP 11201 Zitoune, Meknes, Morocco
3 EST Khenifra, Sultan Moulay Slimane University, Khenifra, BP 170, 54000 Khenifra, Morocco
Licence : CC-BY 4.0
Droits d'auteur : Les auteurs conservent leurs droits
@article{CRCHIM_2020__23_4-5_329_0,
     author = {Habiba Gu\'edouar and Hanane Zaki and Mohammed Bouachrine and Faouzi Aloui},
     title = {Molecular docking investigation of cytotoxic phenanthrene derivatives},
     journal = {Comptes Rendus. Chimie},
     pages = {329--342},
     publisher = {Acad\'emie des sciences, Paris},
     volume = {23},
     number = {4-5},
     year = {2020},
     doi = {10.5802/crchim.27},
     language = {en},
}
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Habiba Guédouar; Hanane Zaki; Mohammed Bouachrine; Faouzi Aloui. Molecular docking investigation of cytotoxic phenanthrene derivatives. Comptes Rendus. Chimie, Volume 23 (2020) no. 4-5, pp. 329-342. doi : 10.5802/crchim.27. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.5802/crchim.27/

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1. Introduction

Polycyclic compounds based on aromatic hydrocarbons are considered attractive targets for synthesizing medicinal units since they exhibit favorable properties such as stability and ease of synthesis and possess high biological responses, particularly anticancer activity [1]. As a result, many researchers around the world have become interested in the preparation and development of new cytotoxic molecules [2, 3, 4]. In this context, H. Guédouar and co-workers [2] worked on the synthesis of a fairly large number of new phenanthrene skeletons, using a simple procedure, with the aim of preparing promising active compounds for the development of anticancer agents. In fact, they prepared a variety of tricyclic compounds by modifying the central structure of phenanthrene. The compounds were evaluated for their in vitro cytotoxic activity against two tumor cell lines. Interestingly, the analysis of the IC50 values suggests that most compounds exert cytotoxic effects with selectivity. Among them, methyl 8-methyl-9,10-phenanthrenequinone-3-carboxylate D-1 (IC50 = 0.97 μg∕mL) and methyl 8-methyldibenzo[a,c]phenazine-3-carboxylate D-2 (IC50 = 1.09 μg∕mL) are interesting substrates due to their highest potency against the Caco-2 cancer cell (Figure 1).

Figure 1.

Chemical structures of the studied phenanthrenes D-1 and D-2.

In this study, molecular docking was performed on the two most active O-linked molecules D-1 and D-2, previously prepared by H. Guédouar and co-workers to identify the key structural features required to design new potent candidates of this class. Thus, the results extracted from this study might be useful to design potent antitumor drugs. Before performing the molecular docking, the studied molecules were optimized using the density functional theory (DFT) method. In recent years, the DFT has become the most popular quantum chemical method for computing several molecular properties such as those exhibited by chemical, physical, and biological systems [5, 6, 7]. The reported quantum chemical calculations were performed at the B3LYP/6-31G(d,p) level of theory [8, 9, 10]. The geometry optimization in the gas phases was carried out using the Gaussian 09 suite of programs [11].

2. Molecular docking study

Molecular docking analysis is a reliable method for the evaluation of binding affinity and the prediction of intermolecular interactions of novel compounds containing potential receptors [12, 13]. We performed molecular docking studies for eight vital cancer targets (Table 1). Our research was based on the crystal structures of receptors with bound ligand molecules. This structure was obtained from X-ray crystal data of RCSB Protein Data Bank (PDB)  [14, 15, 16].

Table 1.

Protein database used for docking study and their native ligands

PDB codeNameNative ligandChain
2HYYHuman Proto-oncogene tyrosine-protein kinase ABL1Imatinib A
3C4CB-Raf proto-oncogene serine/threonine-protein kinasePLX4720 A
3EWHVascular endothelial growth factor receptor 2Pyridyl-pyrimidine benzimidazole A
3RCDReceptor tyrosine-protein kinase erbB-2TAK-285 A
3W2SEpidermal growth factor receptorW2R A
4JT5Serine/threonine-protein kinase mTORTorkinib (PP242) A
4U5JProto-oncogene tyrosine-protein kinase SrcRuxolitinib A
6N2JGTPase KRasTetrahydropyridopyrimidines A

In the majority of selected structures, co-crystallized ligand molecules are known drugs with proven action. Thus they were utilized to predict the binding site location [17] as well as to serve as references in our analysis. As previously demonstrated [2], molecules D-1 and D-2, whose 3D-QSAR structures are shown in Figure 2, are the most active. Docking studies of both compounds were carried out to analyze their ability to interact with each target for which the binding site locations are shown in Table 2.

Each enzyme does not necessarily contain a single active site. We chose the active site of interest to the study, which contains the reference inhibitor (which is the drug site); (X, Y and Z) are the three-dimensional coordinates of the active site of interest (in this case, inhibition of the enzyme).

Table 2.

Binding site location for each target

PDB code X Y Z
2HYY14.25115.28217.632
3C4C0.478−2.111−19.745
3EWH15.131−5.23110.046
3RCD13.0471.81028.168
3W2S5.7260.74812.742
4JT551.856−0.015−49.145
4U5J−8.38226.9095.045
6N2J22.522.591 −22.481

Figure 2.

3D-QSAR structures of compounds D-1 (a) and D-2 (b) used for the docking study.

Figure 3.

3D structure of the native ligand PLX4720.

2.1. Docking results

With the aim of confirming the potential cytotoxicity of our phenanthrene derivatives D-1 and D-2, we evaluated the binding mode and explored their intermolecular interactions with appropriate proteins. The docking results are summarized in Table 3. The binding affinity was evaluated by the binding free energy (Kcal∕mol). In fact, all the studied targets can establish binding with the two studied ligands. The tricyclic compound D-1 exhibited binding energies ranging from −9.8 to − 8.3 kcal∕mol. The molecular docking study with molecule D-2 revealed a binding energy ranging from −11.1 to −9.2 kcal∕mol. This slight difference in energy is probably due to the size of the studied molecules. Indeed, molecule D-1 is tricyclic while D-2 is composed of five cycles, one of which is heterocyclic.

Table 3.

Docking score expressed in kcal∕mol

PDB codeMolecule D-1Molecule D-2
2HYY−8.3−9.2
3C4C−9.8−11.1
3EWH−9.4−10.1
3RCD−9.2−10.3
3W2S−9.0−10.1
4JT5−8.9−10.2
4U5J−9.4−10.4
6N2J−9.0−9.4

Table 4.

Modes and types of bonds between the studied molecules and their potential target

PDB codeD-1D-2
2HYY
3C4C
3EWH
3RCD
3W2S
4JT5
4U5J
6N2J

Figure 4.

Interactions between the protein B-Raf proto-oncogene serine/threonine-protein kinase and molecule D-1 (a), molecule D-2 (b), and the native ligand PLX4720 (c).

Table 5.

Details of the different interactions

TargetD-1D-2TargetD-1D-2
2HYYASP 381 NH–O ligand ALA 380 C–O ligand3W2SMET 793 NH–O ligand LYS 745 NH–O ligand
ALA 330 C–O ligand VAL 299 O–C ligandTHR 854 OH–O ligandLEU 718 C–π ligand
ASP 381 O–π ligandASP 381 O–π ligandLYS 745 C–O ligandVAL 726 C–π ligand
ASP 381 O–π ligandASP 381 O–π ligandGLY 796 C–O ligandVAL 726 C–π ligand
ASP 381 O–π ligandASP 381 O–π ligandLEU 718 C–π ligandLEU 844 C–π ligand
VAL 289 C–π ligandVAL 289 C–π ligandLEU 844 C–π ligandALA 743 π–C ligand
VAL 289 π–C ligandVAL 289 C–π ligandLEU 718 π–C ligandLEU 844 π–C ligand
ILE 293 ππ ligandMET 290 ππ ligandVAL 726 ππ ligandLEU 844 ππ ligand
VAL 289 ππ ligandALA 743 ππ ligandLEU 718 ππ ligand
VAL 726 ππ ligandVAL 726 ππ ligand
ALA 743 ππ ligandLEU 844 ππ ligand
LEU 844 ππ ligandVAL 726 ππ ligand
VAL 726 ππ ligandALA 743 ππ ligand
3C4C LYS 483 NH–O ligandASP 594 NH–O ligand4JT5LEU 2185 C–π ligandLYS 2187 NH–N ligand
TRP 531 ππ ligandVAL 471 C–π ligandMET 2345 C–π ligandASP 2357 N–π ligand
PHE 583 ππ ligandVAL 471 C–π ligandILE 2356 C–π ligandILE 2237 C–π ligand
PHE 583 ππ ligandTRP 531 ππ ligandTRP 2239 ππ ligandILE 2356 C–π ligand
PHE 583 ππ ligandPHE 583 ππ ligandTYR 2225 ππ ligandILE 2356 C–π ligand
TRP 531 π–C ligandPHE 583 ππ ligandTYR 2225 ππ ligandILE 2356 C–π ligand
VAL 471 ππ ligandPHE 583 ππ ligandMET 2345 π–C ligandILE 2356 C–π ligand
LYS 483 ππ ligandPHE 583 ππ ligandILE 2237 ππ ligandLEU 2195 π–C ligand
VAL 471 ππ ligandTRP 531 π–C ligandILE 2356 ππ ligandMET 2345 π–C ligand
VAL 471 ππ ligandVAL 471 ππ ligandLEU 2285 ππ ligandTRP 2239 π–C ligand
ALA 481 ππ ligandVAL 471 ππ ligandILE 2237 ππ ligandILE 2356 ππ ligand
LEU 514 ππ ligandVAL 471 ππ ligandILE 2356 ππ ligandLEU 2185 ππ ligand
CYS 532 ππ ligandLYS 483 ππ ligandILE 2237 ππ ligand
ALA 481 ππ ligandLEU 2185 ππ ligand
CYS 532 ππ ligandLEU 2185 ππ ligand
MET 2345 ππ ligand
3EWHTHR 916 OH–O ligandLEU 840 C–π ligand4U5JTHR 338 OH–O ligandLYS 295 NH–O ligand
CYS 919 NH–O ligandVAL 848 C–π ligandMET 341 NH–O ligandLEU 273 C–π ligand
VAL 848 C–π ligandVAL 848 C–π ligandASP 348 OH–C ligandVAL 281 C–π ligand
PHE 918 ππ ligandLEU 1035 C–π ligandLEU 273 C–π ligandVAL 281 C–π ligand
PHE 1074 ππ ligandPHE 1047 ππ ligandVAL 281 C–π ligandLEU 393 C–π ligand
LEU 840 ππ ligandPHE 1047 ππ ligandLEU 393 C–π ligandALA 293 π–C ligand
LEU 1035 ππ ligandALA 866 π–C ligandLYS 295 π–C ligandMET 341 π–C ligand
LEU 1035 ππ ligandLEU 840 ππ ligandVAL 323 π–C ligandLEU 393 π–C ligand
LEU 840 ππ ligandALA 866 ππ ligandLEU 393 ππ ligandTYR 340 C–π ligand
ALA 866 ππ ligandLEU 1035 ππ ligandVAL 281 ππ ligandLEU 393 ππ ligand
ALA 866 ππ ligandLEU 840 ππ ligandALA 293 ππ ligandLEU 273 ππ ligand
ALA 866 ππ ligandLYS 295 ππ ligandVAL 281 ππ ligand
CYS 919 ππ ligandLEU 393 ππ ligandLEU 393 ππ ligand
VAL 281 ππ ligand
VAL 293 ππ ligand
LYS 295 ππ ligand
3RCDTHR 862 OH–O ligandTHR 862 OH–O ligand6N2J ALA 18 NH–O ligand SER17 N–O ligand
ALA 751 OH–C ligand ALA 571 O–C ligand SER 17 C–O ligand ALA 18 N–O ligand
LEU 796 O–C ligand LEU 796 O–C ligandLYS 117 N–π ligandLYS 117 N–π ligand
VAL 734 C–π ligandVAL 734 C–π ligandPHE 28 ππ ligandLYS 117 N–π ligand
LEU 852 C–π ligandLEU 852 C–π ligandPHE 28 ππ ligandLYS 117 N–π ligand
LEU 726 π–C ligandLEU 726 π–C ligandLYS 117 π–C ligandLYS 117 N–π ligand
PHE 1004 π–C ligandPHE 1004 π–C ligandLEU 120 π–C ligandPHE 28 ππ ligand
VAL 734 ππ ligandVAL 734 ππ ligandALA 18 ππ ligandPHE 28 ππ ligand
ALA 751 ππ ligandALA 751 ππ ligandLYS 117 ππ ligandLYS 117 π–C ligand
LYS 753 ππ ligandLYS 753 ππ ligandALA 18 ππ ligandLEU 120 π–C ligand
ALA 751 ππ ligandALA 751 ππ ligandLYS 117 ππ ligandLYS 147 π–C ligand
LEU 852 ππ ligandLEU 852 ππ ligandALA 146 ππ ligandALA 18 ππ ligand
ALA 751 ππ ligandVAL 734 ππ ligandLYS 147 ππ ligandLYS 117 ππ ligand
ALA 751 ππ ligandALA 18 ππ ligand
VAL 734 ππ ligandLYS 117 ππ ligand
ALA 146 ππ ligand

In addition, the data shown in Table 3 indicate that both molecules show a very high affinity to and stability with all the studied targets. In particular, the highest affinity is noted for the protein B-Raf proto-oncogene serine/threonine-protein kinase (PDB code 3C4C) [18, 19]. In fact, the affinity between molecule D-1 and 3C4C is found to be about −9.8 Kcal∕mol. The affinity between 3C4C and molecule D-2 is about −11.1 Kcal∕mol. We can conclude from these results that the B-Raf protein is the most likely target for this molecule. Thus, it is worth noting that this protein is involved in sending signals inside cells that are involved in directing cell growth. It regulates cell proliferation and growth, cell survival, cell mobility, protein biosynthesis, and transcription, which suggests that it is the most targeted protein by our tricyclic molecule.

Moreover, it is believed that the remarkable activity of molecules D-1 and D-2 is related to their stability, which is explained by the numbers and types of bonds established with the studied potential targets. These descriptors are mentioned in Table 4, and the details of the interactions are presented in Table 5. In this regard, the amino acids VAL 471, PHE 583, LYS 483, ALA 481, and TRP 531 are found to be important for the antiproliferative activity of our molecules since they form bonds in both cases. As expected for 3C4C, it appears that the hydrogen bond formed with the amino acid ASP 594 increases affinity to the target, which in turn increases the activity of both molecules.

The positioning of each molecule in the active site and the binding pocket are shown in Table 6.

Table 6.

Positioning and the binding pocket of each molecule in the active site

PDB codeD-1D-2
2HYY
3C4C
3EWH
3RCD
3W2S
4JT5
4U5J
6N2J

Based on affinity, stability, and the study of different interactions, we can ensure that B-Raf proto-oncogene serine/threonine-protein kinase is the potential target for these molecules. To better confirm these results, we have compared the types and numbers of bonds of our molecules D-1 and D-2 with those of the native ligand PLX4720 (Figure 3).

It can be seen from the comparison of the interactions between the potential target and the studied molecules as well as the reference molecule that most of the amino acids that interact with the reference molecule also interact with our studied molecules. These interactions are essentially hydrophobic bonds, hydrogen bonds, and π-interactions (Figure 4).

3. Conclusion

Following the study of H. Guédouar and co-workers that evaluated the antiproliferative activity of phenanthrene derivatives against the Caco-2 cancer cell line, this study proposed two molecules that exhibited the best activity against this cancerous cell. For understanding the mode of action of these molecules to propose a potential therapeutic target in the two types of studied cancers, we established molecular docking against eight vital cancer targets. As a result, molecular docking results confirmed that tricyclic molecules D-1 and D-2 show significant activity. Both of the studied compounds were found to display low binding energies and the best affinity is noted in the protein B-Raf proto-oncogene serine/threonine-protein kinase, which is an important target in both types of studied cancers. Moreover, the comparison of the types and the modes of interactions between these molecules and the reference ligand, which is an inhibitor of this protein, shows remarkable similarity in the binding of amino acids in the types of interactions, which suggests that molecules D-1 and D-2 are ligands that can inhibit this protein.

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