derivative) could modify the expression of the androgen receptor in an androgen-dependent cell line, resulting in the regulation of prostate cell growth.^[32] However, a study displayed that both (R)-methanandamide and WH-015 drug decreasing prostate cancer though CB2 cannabinoid-receptor using a PC-3 cell line (human prostate epithelial cells).^[33] All this data suggests that some cannabinoid derivatives can produce effects on prostate cancer; however, the possible effect exerted on either androgen receptor, or 5-a reductase enzyme is very confusing; perhaps, this phenomenon is due to differences in the chemical structure of cannabinoids. Analyzing this hypothesis. The aim of this theoretical study was to evaluate the possible interaction of twenty-cannabinoids derivatives on either androgen receptor or 5a-reductase enzyme using testosterone, dihydrotestosterone, flutamide, dutasteride, and finasteride drugs as theoretical tools in a Docking model.

Materials and Methods

Twenty-cannabinoid derivatives were used as theoretical tools (Figure 1) to evaluate their possible interaction with either androgen receptor or 5a-reductase enzyme as follows:

1 = Cannabigerol

2 = Cannabigerol monomethyl ether

3 = Cannabinerolic acid

4 = Cannabigerovarin

5 = Cannabigerolic acid

6 = Cannabigerovarinic acid

7 = Cannabichromene

8 = Cannabichromenic acid

9 = Cannabivarichromene

10 = Cannabichromevarinic acid

11 = Cannabidiol CBD-C₅

12 = Cannabidiol monomethyl ether

13 = Cannabidiol

14 = Cannabidivarin

15 = Cannabidiorcol

16 = Cannabidiolic acid

17 = Cannabidivarinic acid

18 = Cannabinodiol

19 = Cannabinodivarin

20 = Dronabinol

Ligand-protein complex

The interaction of opioid derivatives with either androgen receptor or 5a-reductase enzyme surface was evaluated using either 3L3X (PDB DOI: 10.2210/pdb3L3X/pdb)^[34] or 7BW1 (PDB DOI: 10.2210/pdb7BW1/pdb)^[35] proteins as theoretical models. Besides, to evaluate the different types of binding energy involved in opioid derivative-protein complex formation, the DockingServer program was used.^[36]

Pharmacokinetics parameter

Some Pharmacokinetic involved in the chemical structure of cannabinoid derivatives (1, 3, 6, 13, 16, 18 and 20) were determined using the SwissADME software.^[37]

Toxicity analysis

Theorethical toxicity produced by either cannabinoid derivatives (1, 3, 6, 13, 14, 16, 18 and 20) was determined using GUSAR software.^[38]

Results and Discussion

Protein-ligand analysis

Several methods to predict the interaction of several drugs with androgen receptor such as Gold,^[39] Glide,^[40] Autodock,^[41] and DockigServer^[42] have reported. For example, a theoretical study indicates that hormone-binding site which is well-characterized as a hydrophobic cavity that forms strong hydrophobic interactions with a steroidal core of androgens.^[43] Another report showed that amino acid residues such as Asn705 and Thr877 may involve hydrogen bond interactions with the 17-hydroxy group of testosterone and Gln711 and Arg752 with the 3-keto group of this androgen.^[44] In addition, a theoretical study suggests that some cannabinoids such as tetrahydrocannabinol and cannabidiol may have biological activity on androgen receptor translated as an inhibition of prostate cancer progression.^[45] Analyzing these data, and other studies which suggest that cannabinoids may reduce prostate cancer;^{[28, 30-33]} in this investigation twenty cannabinoid derivatives were used to evaluate their interaction with androgen receptor using at 3L3X protein as theoretical model. The results (Table 1) showed that interaction of cannabinoid derivatives with 3L3X protein surface could possibly involve some different aminoacid-residues compared to testosterone, dihydrotestosterone and flutamide.

However, it is important to mention that a study showed that some thermodynamic parameters are involved in the interaction of testosterone and its analogues on the androgen receptor.^[46] For this reason, in this study several energy parameters (Table 2) for cannabinoid derivatives, testosterone, dihydrotestosterone and flutamide were evaluated using DockingServer program.

Flu = Flutamide

Test = Testosterone

DHT = Dihydrotestosterone

I = Free Energy of Binding (kcal/mol)

II = Inhibition Constant, Ki (mM)

III = Vander Waals forces + H-bond + desolv Energy (kcal/mol)

IV = Electrostatic Energy (kcal/mol)

V = Total Intermolecular Energy (kcal/mol)

VI = Interaction Surface

The results showed differences in bond-energy levels for cannabinoid derivatives, testosterone, dihydrotestosterone and flutamide. Besides, the inhibition constant (Ki) was lower for cannabinoid derivatives 6, 13, 16 and 20 compared to testosterone dihydrotestosterone and flutamide; these data suggest that these cannabinoid analogues could act as androgen receptor inhibitors, resulting in a decrease in prostate cancer. However, it is noteworthy that other molecular mechanisms are involved in the development of prostate cancer; for example, several studies indicate that some drugs such as dutasteride and finasteride (5a-reductase enzyme inhibitors)^{[14, 47]} can decrease prostate cancer. Analyzing these data, the aim of this research was to evaluate the theoretical interaction of cannabinoid derivatives (Compound 1 to 20) on 5a-reductase enzyme using at 7BW1 protein, dutasteride and finasteride as theoretical tools (Table 3). 

Flu = Flutamide

Test = testosterone

The results showed differences in some aminoacid residues for cannabinoid derivatives compared with dutasteride and finasteride. Besides, the Ki for cannabinoid analogs such as 1, 3, 14 and 18 was lower compared with dutasteride and finasteride (Table 4); These data suggest that these cannabinoid derivatives could act as 5a-reductase enzyme inhibitors, producing a decrease in prostate cancer.

Com = Compound

Dut = Dutasteride

Finast = Finasteride

I = Free Energy of Binding (kcal/mol)

II = Inhibition Constant, Ki (mM)

III = Vander Waals forces + H-bond + desolv Energy (kcal/mol)

IV = Electrostatic Energy (kcal/mol)

V = Total Intermolecular Energy (kcal/mol)

VI = Interaction Surface

Pharmacokinetic analysis

Pharmacokinetic characteristics is an area which have been focused on quantitative pharmacological studies for anticancer drugs.^[48] It is important to mention that several theoretical methods have been used to predict some pharmacokinetic parameters, such as PKQuest^[49] PharmPK,^[50] and SwissADME.^[51] Analyzing these data, in this investigation, some pharmacokinetic parameters for cannabinoid derivatives 1, 3, 6, 13, 14, 16, 18 and 20 were evaluated using the SwissADME program. Theoretical results (Table 5) show differences in gastrointestinal absorption and metabolism involving some cytochrome P450 systems; this phenomenon could depend on the chemical structure of the cannabinoid derivatives and their degree of lipophilicity.

Toxicity analysis

Some methods have been used to predict the degree of toxicity of various compounds such as ADME/Tox,^[52] eToxPred,^[53] GUSSAR.^[54] Analyzing these data, the aim of this study was to evaluate the possible toxic effect produced by cannabinoid derivatives 1, 3, 6, 13, 14, 16, 18 and 20 using the GUSSAR software. The results (Table 6) suggest that lower doses of cannabinoid derivatives are needed (via oral) to produce toxicity compared to testosterone and dihydrotestosterone. Besides, other data indicate that compounds 13, 14, 16 and 20 require low doses to induce toxicity compared with dutasteride and finasteride.

Com = Compound

Flu = Flutamide

Test = Testosterone

DHT = Dihydrotestosterone

Dut = Dutasteride

Finast = Finasteride

IP = Intraperitoneal.

IV = Intravenous.

Oral = Oral.

 SC = Subcutaneous.

Conclusion

In this investigation, the theoretical interaction of twenty cannabinoid derivatives with the androgen receptor or 5α-reductase enzyme was determined. Theoretical interaction showed higher affinity of cannabinoid derivatives 6, 13, 16 and 20 for the androgen receptor surface compared to testosterone, dihydrotestosterone and flutamide. Besides, other results suggest that cannabinoid derivatives 1, 3, 14 and 18 could have higher affinity by 5a-reductase enzyme compared with dutasteride and finasteride. All these data suggest that cannabinoid derivatives 6, 13, 16 and 20 could act as androgen receptor inhibitors. In addition, the cannabinoid analogs 1, 3, 14 and 18 could exert their biological activity as 5a-reductase enzyme inhibitors. This phenomenon could be translated as good candidates for the treatment of breast cancer.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

None.

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