Theoretical evaluation of interaction of some dibenzo derivatives on both androgen receptor and 5α-reductase enzyme

Lauro Figueroa-Valverde¹, Marcela Rosas-Nexticapa², Magdalena Alvarez-Ramirez², Maria Lopez-Ramos¹, Virginia Mateu-Armand^2*

¹Pharmacochemistry Research Laboratory, Faculty of Biological-Chemical Sciences, University Autonomous of Campeche; Humberto Lanz Cárdenas s/n, Ex Hacienda Kalá, C.P. 24085, Campeche, Mexico. ²Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico.

Abstract

There are several drugs to treat cancer; nevertheless, some can produce adverse effects, such as hypertension, hepatic injury, and erectile dysfunction. In the search for new therapeutic alternatives, some Dibenzo derivatives have been used for treating cancer; however, other data suggest that Dibenzo derivatives can increase this clinical pathology. All these data are confusing; perhaps this phenomenon is due to the different chemical structures of each Dibenzo-derivative. Analyzing this data, this research aimed to evaluate the possible interaction of some Dibenzo derivatives (compounds 1 to 15) on some biomolecules involved in prostate cancer, such as androgen receptor and 5α-reductase enzyme using flutamide, dutasteride, and finasteride drugs as theoretical tools in a Docking model. The results showed that some Dibenzo derivatives (9, 11, and 15) could interact with the androgen receptor surface. Besides, the Dibenzo derivatives 2, 5, and 13 may interact with the 5α-reductase enzyme surface. In conclusion, these data suggest that some Dibenzo derivatives could be good candidates for the treatment of prostate cancer.

Keywords: Cancer, Dibenzo, Androgen, 5α-reductase

receptor androgen inhibition.^[22] Besides, a report showed that urolithins, hydroxylated derivatives of 6 H-dibenzo[b;d]pyran-6-one, reduce LNCaP cell proliferation compared with some antiandrogens drugs.^[23] All this data suggests that several drugs produce effects on prostate cancer; however, the effect produced by these compounds involves different mechanisms of action; this phenomenon could be due to the different chemical structures of each drug.

The objective of this investigation was to evaluate the possible interaction of some Dibenzo derivatives on both androgen receptor and 5a-reductase enzyme using flutamide, dutasteride, and finasteride drugs as theoretical tools in a Docking model through the analysis of this data.

Materials and Methods

Fifteen Dibenzo derivatives (Figure 1) were used to evaluate the possible interaction with both the androgen receptor and 5a-reductase enzyme as follows:

Ligand-protein interaction

The interaction of Dibenzo derivatives with both androgen receptor and 5a-reductase enzyme surface was evaluated using either 4fdh^[39] or 7bw1^[40] proteins as theoretical models. In addition, to evaluate the types of binding energy involved in the interaction of Dibenzo derivatives with either 4fdh or 7bw1 proteins surface, the DockingServer software was used.^[41]

Pharmacokinetics parameter

Pharmacokinetic parameters were determined using the SwissADME software.^[42]

Toxicity evaluation

Possible toxicity produced by either Dibenzo[b,e]thiophen-11(6H)-one was determined using GUSAR software.^[43]

Results and Discussion

It is important to mention that several reports in the literature indicate that Dibenzo derivatives can exert anti-cancerogenic activity;^[44] however, contrary to this data, some studies indicate that different Dibenzo derivatives may produce mutagenic effects using some biological models.^[45] All these data are confusing; perhaps this phenomenon is due to i) differences in the chemical structure of each Dibenzo derivative, ii) different sites of its action, or iii)  different concentrations and routes of administration. Analyzing all these data and other studies which indicates that some dibenzo-p-dioxins may increase the incidence of prostate cancer by interacting with the androgen receptor.^[20-22] For this reason, in this study, the interaction of fifteen Dibenzo derivatives on androgen receptors was evaluated using 4fdh protein^[39] and flutamide (Androgen receptor inhibitor)^[2] as a theoretical tool in a Docking model.^[41]

The results (Table 1 and Figure 2) showed that flutamide interacts with different amino acid residues involved in the 4fdh protein surface compared with Dibenzo derivatives (1 to 15); this data suggest that this interaction is due to different functional groups involved in the chemical structure of each Dibenzo derivatives (Tables 1-3 and Figure 2). 

However, it is important to mention that several reports suggest that the energy levels involved in the interaction protein-ligand must be considered to determine the stability of the protein-ligand complex.^[41] In this way, some studies indicate that i) free energy of binding, which determines the energy value that requires a molecule to interact with a protein in a water environment; ii) Electrostatic energy is the product of electrical charge and electrostatic potential, which are involved in the ligand-protein system; iii) total intermolecular energy; and iv) van der Waals (vdW) + hydrogen bond (H-bond) + desolvation energy (which have an influence on the movement of water molecules into or out of the ligand-protein system).^[41] This research determined different thermodynamic factors involved in the interaction of Dibenzo-derivatives with 4fdh protein surface using an androgen receptor inhibitor (flutamide) as control. The results (Table 2) showed that the inhibition constant for compounds 9, 11, and 14 was lower compared to flutamide, compounds 1-8, 10, and 12-14, which may result in greater interaction with the 4fdh protein surface. This phenomenon could produce changes in the biological activity of androgen receptors, translating into a possible decrease in prostate cancer levels.

A = Est: Free Energy of Binding (kcal/mol)

B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol)

D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol)

F = Interact. Surface

However, it is important to mention that other biomolecules, such as the 5(-reductase enzyme, are involved in the development of prostate cancer. In this way, a study showed that some Dibenzo derivatives could modulate the 5α-reductase enzyme levels in a human prostatic carcinoma cell line.^[46] In this research, the theoretical activity of Dibenzo derivatives was determined using 7bw1 protein,^[40] dutasteride, and finasteride drugs (5a-reductase enzyme inhibitors)^[7] as a theoretical tool on DockingSever software. The results show different amino acid residues involved in the interaction between Dibenzo derivatives (compound 1 to 15) with 7bw1 protein surface compared with dutasteride and finasteride (Table 3 and Figure 2).

Finally, the thermodynamic analysis of Dibenzo derivatives (Table 4) showed that the inhibition constant of compound 13 was lower compared with finasteride. In addition, compounds 2, 5 and 13 showed differences in constant inhibition levels compared with dutasteride. All these data suggest that 2, 5, and 13 could have higher affinity by 7bw1 protein surface, which may translate as 5α-reductase enzyme inhibition resulting in decreasing prostate cancer levels.

A = Est: Free Energy of Binding (kcal/mol)

B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol)

D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol)

F = Interact. Surface

Pharmacokinetic evaluation

For several years, different protocols have been used to predict some pharmacokinetic parameters, such as PKQuest,^[47] PharmPK,^[48] and SwissADME.^[49] In this study, some pharmacokinetic factors involved in Dibenzo derivatives were analyzed usingSwissADME software (Table 5).

The results displayed differences in gastrointestinal absorption and metabolism (involving different types of cytochrome P450 systems). This phenomenon could depend on the chemical structure of each Dibenzo derivative.

Toxicity analysis

Some data in the literature indicate that some Dibenzo derivatives can produce toxicity in different biological models.^[50] Analyzing this data, the possible toxicity produced by some Dinenzo derivatives (2, 5, 9, 11, 13, and 15) was evaluated using the GUSAR software.^[49] The results showed that compound 5 require higher dose to produce toxicity (LD50) via oral (2182 mg/kg) and intravenous (110.10 mg/kg) compared with compounds 2 (oral, 66.17 mg/kg; intravenous 1086 mg/kg), 9 (oral, 1621 mg/kg; intravenous 61.34 mg/kg), 11(oral, 1496 mg/kg; intravenous 88.69 mg/kg), 13 (oral, 1496 mg/kg; intravenous 89.69 mg/kg) and 15 (oral, 305.20 mg/kg; intravenous 73.18 mg/kg). This data suggest that toxicity could be dose-dependent and the routes of administration for each Dibenzo derivative.

Conclusion

Theoretical analyzes on the interaction of Dibenzo derivatives with the 4fdh protein surface suggest that Dibenzo derivatives 9, 11, and 15 might have a higher affinity for 4fdh translated as greater androgen receptor inhibition, possibly resulting in the decrease of prostate cancer levels. Besides, other studies suggest that Dibenzo derivatives such as 2, 5, and 13 could act as 5α-reductase inhibitors in prostate cancer.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

None.

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