Theoretical Evaluation of Twenty-Cannabinoid Derivatives on Either Androgen Receptor or 5α-Reductase Enzyme

Maria Lopez-Ramos¹, Lauro Figueroa-Valverde¹, Francisco Diaz-Cedillo², Marcela Rosas-Nexticapa³, Magdalena Alvarez-Ramirez³

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. ²Laboratory of Organic chemistry, Biological Sciences, National Politechnic Institute; Prolongacion de Carpio y Plan de Ayala s/n, Col. Sto Tomas, 11340, Mexico. ³Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico.

Abstract

There are studies which suggest that some cannabinoids derivatives can produce effects on prostate cancer; however, the effect exerted on androgen receptor and 5a-reductase is very confusing; perhaps, this phenomenon is due to differences in the chemical structure of cannabinoids. The aim of this theoretical research was to evaluate the possible interaction of twenty-cannabinoids derivatives (compounds 1 to 20) with either androgen receptor or 5a-reductase enzyme using either 3L3X or 7BW1 proteins as the theoretical models. Besides, testosterone, dihydrotestosterone, dutasteride, finasteride and flutamide drugs were used as theoretical tools. The results showed higher affinity of cannabinoid derivatives 6, 13, 16 and 20 for the androgen receptor surface compared to testosterone, dihydrotestosterone and flutamide. In addition, other data indicate 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 prostate cancer.

Keywords: Prostate cancer, Cannabinoid, Androgen receptor, 5α-reductase

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)^{[47, 48]} 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.^[49] It is important to mention that several theoretical methods have been used to predict some pharmacokinetic parameters, such as PKQuest^[50] PharmPK,^[51] and SwissADME.^[52] 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,^[53] eToxPred,^[54] GUSSAR.^[55] 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.

1.        Xia C, Dong X, Li H, Cao M, Sun D, He S, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J. 2022;135(5):584-90.

2.        Siegel R, Miller K, Fuchs H, Jemal A. Cancer statistics, 2022. Cancer J Clin. 2022;72(1):7-33.

3.        Saad M, Mokrab Y, Halabi N, Shan J, Razali R, Kunji K, et al. Genetic predisposition to cancer across people of different ancestries in Qatar: A population-based, cohort study. Lancet Oncol. 2022;23(3):341-52.

4.        Lazarus E, Bays H. Cancer and obesity: an obesity medicine association (OMA) clinical practice statement (CPS) 2022. Obesity Pill. 2022;3:100026.

5.        Kobayashi L, Westrick A, Doshi A, Ellis K, Jones C, LaPensee E, et al. New directions in cancer and aging: State of the science and recommendations to improve the quality of evidence on the intersection of aging with cancer control. Cancer. 2022;128(9):1730-7.  

6.        Yoo J, Han K, Shin D, Kim D, Kim B, Chun S, et al. Association Between Changes in Alcohol Consumption and Cancer Risk. J Am Med Assoc. 2022;5(8):2228544.

7.        Dehm S, Tindall D. Molecular regulation of androgen action in prostate cancer. J Cell Biochem. 2006;99(2):333-44.

8.        Babaei H, Sepahy AA, Amini K, Saadatmand S. The Effect of Titanium Dioxide Nanoparticles Synthesized by Bacillus tequilensis on clb Gene Expression of Colorectal Cancer-causing Escherichia coli. Arch Pharm Pract. 2020;11(1):22-31.

9.        Van-Winden L, Van Rossum H. Testosterone analysis in prostate cancer patients. Adv Clin Chem. 2022;108:73-104.

10.      Nallapu M, Vadluri R, Arasan J. Design, and synthesis of new Nilutamide-1, 2, 3-triazole derivatives as in vitro anticancer agents. Chem Biol Lett. 2022;9(4):405.

11.      Bilusic M, Toney N, Donahue R, Wroblewski S, Zibelman M, Ghatalia P, et al. A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1). Prostate Cancer Prostatic Dis. 2022:1-6.

12.      Powles T, Yuen K, Gillessen S, Kadel Iii E, Rathkopf D, Matsubara N, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022;28(1):144-53.

13.      Wenzel M, Nocera L, Colla Ruvolo C, Wuernschimmel C, Tian Z, Shariat S, et al. Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Prostate Cancer. 2022;25(2):139-48.

14.      Björnebo L, Nordström T, Discacciati A, Palsdottir T, Aly M, Grönberg H, et al. Association of 5α-reductase inhibitors with prostate cancer mortality. J Am Med Assoc. 2022;8(7):1019-26.

15.      Obinata D, Nakahara K, Yoshizawa T, Mochida J, Yamaguchi K, Takahashi S. Characteristics of prostate biopsy in patients under the dutasteride treatment. Medicine. 2022;101(44):e31658.

16.      Delaere K, Thillo E. Flutamide monotherapy as primary treatment in advanced prostatic cancer. Seminars Oncol. 1991;18(5 Suppl 6):13-8.

17.      Gomez J, Dupont A, Cusan L, Tremblay M, Tremblay M, Labrie F. Simultaneous liver and lung toxicity related to the nonsteroidal antiandrogen nilutamide (Anandron): a case report. Am J Med. 1992;92(5):563-6.

18.      Boelsterli U, Ho H, Zhou S, Yeow K. Bioactivation and hepatotoxicity of nitroaromatic drugs. Curr Drug Metab. 2006;7(7):715-27.

19.      Taniguchi H, Inoue T, Kawa G, Murota T, Tsukino H, Yoshimura K, et al. Evaluation of sexual function after dutasteride treatment in patients with once negative prostate biopsy and benign prostate hyperplasia. J Sex Med. 2022;19(5):S215.

20.      Ohtsu H, Xiao Z, Ishida J, Nagai M, Wang H, Itokawa H, et al. Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents. J Med Chem 2002;45(23):5037-42.

21.      Algarni SB, Alsugair MM, Alkhars MK, Addas MJ, Hakeem MA, AlSalman AA, et al. Evaluation role of imaging studies in the staging of breast cancer. Arch Pharm Pract. 2020;11(4):70-5.

22.      Jung M, Ouk S, Yoo D, Sawyers C, Chen C, Tran C, et al. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem. 2010;53(7):2779-96.

23.      Kurdi L, Alhusayni F. Cytotoxicity effect of 5-fluorouracil and bee products on the MCF-7 Human Breast Cancer Cell Line in vitro. Int J Pharm Phytopharmacol Res. 2020;10(2):19-26.

24.      Alhashmi M, Alshaikhi R. Hepatotoxicity in Cancer Patients Receiving Anthracyclin at KAUH: A Retrospective Study. Int J Pharm Phytopharmacol Res. 2020;10(2):82-7.

25.      Zhang Z, Connolly P, Lim H, Pande V, Meerpoel L, Teleha C, et al. Discovery of JNJ-63576253: a clinical stage androgen receptor antagonist for F877L mutant and wild-type castration-resistant prostate cancer (mCRPC). J Med Chem. 2021;64(2):909-24.

26.      Salem O, Frotscher M, Scherer C, Neugebauer A, Biemel K, Streiber M, et al. Novel 5α-reductase inhibitors: synthesis, structure− activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids. J Med Chem. 2006;49(2):748-59.

27.      Figueroa-Valverde L, Rosas-Nexticapa M, Alvarez-Ramirez M, Lopez-Ramos M, Mateu-Armand V. Theoretical evaluation of interaction of some dibenzo derivatives on both androgen receptor and 5α-reductase enzyme. Clin Cancer Investig J. 2022;11(5):11-6.

28.      De-Petrocellis L, Ligresti A, SchianoMoriello A, Iappelli M, Verde R, Stott C, et al. Non‐THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro‐apoptotic effects and underlying mechanisms. British J Pharmacol. 2013;168(1):79-102.

29.      Uddin I, Rachana N, Suraj N, Naveena N, Mounica P. Screening anticancer activity of colchicine loaded chitosan nanoparticles. Pharmacophore. 2019;10(2):37-42.

30.      Sarfaraz S, Afaq F, Adhami V, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005;65(5):1635-41.

31.      Morales P, Vara D, Gomez-Canas M, Zuniga M, Olea-Azar C, Goya P, et al. Synthetic cannabinoid quinones: Preparation, in vitro antiproliferative effects and in vivo prostate antitumor activity. Eur J Med Chem. 2013;70:111-9.

32.      Brown I, Cascio M, Wahle KW, Smoum R, Mechoulam R, Ross RA, et al. Cannabinoid receptor-dependent and-independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and-negative prostate cancer cell lines. Carcinogenesis. 2010;31(9):1584-91.

33.      Diaz-Laviada I. The endocannabinoid system in prostate cancer. Nat Rev Urol. 2011;8(10):553-61.

34.      Zhou X, Suino-Powell K, Li J, He Y, MacKeigan J, Melcher K, et al. Identification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor. J Biol Chem. 2010;285(12):9161-71.

35.      Xiao Q, Wang L, Supekar S, Shen T, Liu H, Ye F, et al. Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride. Nat Commun. 2020;11(1):5430.

36.      Figueroa-Valverde L, Rosas-Nexticapa M, Montserra M, Díaz-Cedillo F, López-Ramos M, Alvarez-Ramirez M, et al. Synthesis and Theoretical Interaction of 3-(2-oxabicyclo [7.4. 0] trideca-1 (13), 9, 11-trien-7-yn-12-yloxy)-steroid Deriva-tive with 17β-hydroxysteroid Dehydrogenase Enzyme Surface. Biointerface Res Appl Chem. 2023;13:266.

37.      Mekky A, Sanad S, Abdelfattah A. Tandem synthesis, antibacterial evaluation and SwissADME prediction study of new bis (1, 3, 4-oxadiazoles) linked to arene units. Mendeleev Comm. 2022;32(5):612-4.

38.      Da-Rocha M, Marinho E, Marinho M, Dos-Santos H. Virtual screening in pharmacokinetics, bioactivity, and toxicity of the amburana cearensis secondary metabolites. Biointerface Res Appl Chem. 2022;12:8471-91.

39.      Thieme D, Anielski P, Rzeppa S, Wolf C, Wolber G, Keiler A. Detection of 18‐methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements. Drug Test Anal. 2022:1-17.

40.      Li H, Hassona M, Lack N, Axerio-Cilies P, Leblanc E, Tavassoli P, et al. Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer. Mol Cancer Ther. 2013;12(11):2425-35.

41.      Serçinoğlu O, Bereketoglu C, Olsson P, Pradhan A. In silico and in vitro assessment of androgen receptor antagonists. Comp Biol Chem. 2021;92:107490.

42.      D’Arrigo G, Gianquinto E, Rossetti G, Cruciani G, Lorenzetti S, Spyrakis F. Binding of androgen-and estrogen-like flavonoids to their cognate (non) nuclear receptors: a comparison by computational prediction. Molecules. 2021;26(6):1613.

43.      Li H, Ren X, Leblanc E, Frewin K, Rennie P, Cherkasov A. Identification of novel androgen receptor antagonists using structure-and ligand-based methods. J Chem Inf Mod. 2013;53(1):123-30.

44.      Marhefka C, Moore B, Bishop T, Kirkovsky L, Mukherjee A, Dalton J, et al. Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands. J Med Chem. 2001;44(11):1729-40.

45.      Mobisson, S, Ikpi D, Wopara I, Obembe A, Omotuyi O. Inhibition of human androgen receptor by delta 9‐tetrahydro‐cannabinol and cannabidiol related to reproductive dysfunction: A computational study. Andrologia. 2002;54(8):e14454.

46.      Samchenko A, Komarov V, Kondratyev M. The Study of Steroid Keys for Androgen Receptors. Biophysics. 2021;66:738-45.

47.      Björnebo L, Nordström T, Discacciati A, Palsdottir T, Aly M, Grönberg H, et al. Association of 5α-reductase inhibitors with prostate cancer mortality. J Am Med Assoc Oncol. 2022;8(7):1019-26.

48.      Goodman P, Tangen C, Darke A, Lucia M, Ford L, Minasian L, et al. Long-term effects of finasteride on prostate cancer mortality. New Eng J Med. 2019;380(4):393-4.

49.      Zee-Cheng R, Cheng C. Delivery of anticancer drugs. Meth Find Exp Clin Pharmacol. 1989;11(7-8):439-529.

50.      Levitt D. PKQuest: capillary permeability limitation and plasma protein binding–application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics. BMC Clin Pharmacol. 2002;2(1):1-11.

51.      Ishaku S, Bakare-Odunola M, Musa A, Yakasai I, Garba M, Adzu B. Effect of dihydro-artemisinin on the pharmacokinetics of gliclazide in diabetic subjects. International J Biol Chem Sci. 2020;14(6):2267-76.

52.      Ahmed A, Mekky A, Sanad S. New bis (pyrazolo [3, 4-b] pyridines) and bis (thieno [2, 3-b] pyridines) as potential acetylcholinesterase inhibitors: synthesis, in vitro and SwissADME prediction study. J Iranian Chem Soc. 2022;19(11):4457-71.

53.      Daoui O, Mazoir N, Bakhouch M, Salah M, Benharref A, Gonzalez-Coloma A, et al. 3D-QSAR, ADME-Tox, and molecular docking of semisynthetic triterpene derivatives as antibacterial and insecticide agents. Struct Chem. 2022;33(4):1063-84.

54.      Pu L, Nader, M, Liu T, Wu H, Mukhopadhyay S, Brylinski M. eToxPred: a machine learning-based approach to estimate the toxicity of drug candidates. BMC Pharmacol Toxicol. 2019;20(1):1-15.

55.      Lagunin A, Zakharov A, Filimonov D, Poroikov V. QSAR modelling of rat acute toxicity on the basis of PASS prediction. Mol Inf. 2011;30(2‐3):241-50.