INTRODUCTION:

Hystericalpropagation of abnormal cells in breast tissue is symbol of assorted disease known as breast cancer. Men and women can be affected by it, although women are much more likely to be.¹ There are numerous types of breast cancer and less prevalent subtypes include triple-negative and inflammatory breast cancer. While IDC and ILC refer to cancer cells penetrating the surrounding breast tissue, DCIS refers to aberrant cells in the milk ducts.^2-4 The tumor's size, lymph node involvement, and organ metastases are taken into consideration when staging breast cancer. Prognosis prediction and proper treatment options are aided by staging.⁵ When compared to hormone targeted anti-cancer therapies, their efficacy is believed to be characterised by lower toxicity, safety, and fewer recurrent resistances.^6,7

Fig. 1: Breast cancer condition

In Greek temples dedicated to the god of medicine Asclepius, votive gifts shaped like breasts were placed as proof that a deity was urged to heal illnesses of the breasts.⁸ Hellenistic texts are the source of the medical terminology carcinoma, scirrhous, and cacoethes. Early theories regardingaetiology of cancer include Hippocrates' theory of imbalance of humours as reason of disease and his well-known reports of successive phases of breast cancer.⁹ Breast cancer's complicated past is a patchwork of investigations into the hormone-responsive malignancy and the doggedness with which doctors have battled it through surgical removal, cell lysis, and targeted therapy to cell receptors.¹⁰The body has a 30% relative 5-year survival rate. Compared to White women, Black women had a 9% poorer breast cancer survival rate. When breast cancer is first detected, about 6% of women have cancer that has progressed to regional lymph nodes and the breast.¹⁴ By involving international partners and coordinating sustained efforts to enhance outcomes, in addition to advocating for prompt diagnosis, appropriate treatment, and patient management, WHO and its partners hope to lower the death rate from breast cancer.^15,16,18

Hormonal abnormalities, particularly in the levels of progesterone and oestrogen, have been related to breast cancer. The hormone oestrogen, which the ovaries generate, encourages the growth and development of breast tissue.^19,20 An irregularity or disturbance in the body's ideal hormone levels or ratios is referred to as a hormonal imbalance. Because of variations between individuals and the complexity of hormone interactions, it may be difficult to define a certain statistical ratio or range of hormones as "balanced" or "normal".^21,22,23

By targeting these receptors specifically with medications, we can successfully limit tumour growth and enhance patient outcomes.^24,25 Hormone replacement therapy (HRT), especially combination oestrogen progestin therapy, increases the risk of breast cancer when done over an extended period of time.²⁶ When thinking about using HRT, women should carefully examine the risks and benefits and speak with their healthcare professional.²⁷

Morning Glory plants belong to the Convolvulaceae family, which includes 57 genera and approximately 1600 species. Natural products have demonstrated potential in treating cancer and tumours. Reduced toxicity during use and less recurrent resistance to hormone targeted anti-cancer medicines are further reports of their usefulness.²⁸

MATERIALS AND METHODS:

Ligandcuration and preparation:

PyRx's pub Chem Id was used to derive the planned derivatives from the structures of the Ipomoea Tricolour compounds (Tricolorin A, Elymoclavine, and Isolysergic acid amid) that were retrieved from PubChem for the purpose of studying breast cancer activity. The structures were then docked using the structures that satisfied Veber's Law, the ADME threshold, and the Lipinski rule of five after being crushed into a single SDF file using Open Babel programme.Using online programmes such as SwissADME, the structures were additionally checked for ADME and the Lipinski rank-five rule. The SwissADME reported a wide range of data, including the following: molecular weight, usability score, the amount of rotatable bonds, frequency of hydrogen bond donors and acceptors, topological surface area, and plenty more.

Protein Preparation:

The Protein Data Bank (PDB) provided the NUDT V [Nudix hydrolase-V] structures in pdb download format (PDB ID: 3WVM, 7AM9, 6T81, 7MBO and 5LHW). The protein's active site, ligand site, and amino acid sequence were all determined using the BIOVIA Discovery Studio Visualizer 2021 v21.1.0.20298. In addition, polar hydrogens were added to protein structure, which was preserved in PDB format for docking analysis, while water and other heteroatoms were eliminated.

Molecular Docking Studies: A virtual screening platform called PyRx was provided with the selected substances and protein structures after they were uploaded. The '.pdbqt' format was used to store chemical compounds and protein structures by means of PyRx's Open Babel tool. The active binding site's grid box was constructed using the forward option in PyRx. The size and location of the grid box could be changed by either following its border line or by entering values into the appropriate box. The results of PyRx are partitioned into different conformers with the help of Autodock Vina. Next, we used Discovery Studio Visualizer to examine the docking output files for chemical-protein interactions. Based on a higher non-covalent bond interaction and docking score, the optimal conformer was chosen. Images of the docking position and interactions were gathered while doing this the amino acid label was added and background color was change into white and saved as 2D and 3D image files. Using the SWISSADME online program, their synthetic accessibility and ADME features were also determined.

Theoretical Prediction of ADMETParameters: The compounds that scored highest were exported in SMILES format from the docking simulation to SwissADME and the pkCSM web server. These compounds were then subjected to toxicity and bioavailability prediction methods such as Lipinski's rule of five. ADME characteristics of substances were calculated using the SwissADME web application. This calculation was used to forecast how drug-like the Ipomoea Tricolor compounds employed in the docking analysis would be. Only a comparison between the planned drug qualities and the known drug ADME properties is made.

RESULT AND DISCUSSION:

Molecular Docking Simulations:

According to the findings, there are some naturally occurring compounds with binding energies that surpass those of commonly used pharmaceuticals. What follows is a table listing the binding energies of the three chemicals with the most widely used anticancer medicines. Documentary evidence, including IMPPAT and Wikipedia, led to the discovery of the compounds derived from plants. Ipomoea tricolor's Tricolorin A, Elymoclavine, and isolysergic acid amide all have optimal binding energies, according to the results. Tricolorin A, Elymoclavine, and Isolysergic acid amide were shown to have 3D and 2D structures in conjunction with the five proteins in the study. Tricolorin A, Elymoclavine, and Isolysergic acid amide interact with five proteins' ATP binding sites visible in the picture (pdb ID: 3WVM, 7AM9, 6T81, 7MBO, and 5LHW). There is a substantial increase in the7 binding activity and ligand protein interaction of tricolorin A, elymoclavine, and isolysergic acid amide. The interactions between three compounds and the top five proteins with the strongest binding affinity are shown in the figure below.

Table 1: Docking and Interactions of 5 proteins against 3 Phytochemicals:

Sr. No.	PDB ID	Pub Chem. ID	Binding Affinity	Interacting Residue	Type of Interaction
1	3WVM	12309749	-10.6	THR A:36, THR A:29, THR A:53, PRO A:38	Van der Waals
				TYR A:128, ARG A:126	Conventional Hydrogen Bond
				SER A:55, LYS A:58, LEU A:23, TYR A:19, THR A:53	Carban Hydrogen Bond
				ASP A:76	Pi-Anion
				MET A:20	Pi-Sulfur
				PHE A:16	Pi-Pi T-Shaped
				ALA A:75	Amide- Pi Stocked
				VAL A:25	Pi- Alkyl
		440904	-10.0	SER A:55, PRO A:38, THR A:53, LYS A:58, THR A:29, LEU A: 23, TYR A:19	Van der Waals
				TYR A:128, ARG A:126, THR A:36	Conventional Hydrogen Bond
				ASP A:76	Pi-Anion
				MET A:20	Pi-Sulfur
				PHE A:16	Pi-Pi T-Shaped
				ALA A:75	Pi- Alkyl
		10418553	-9.0	ASP A:18, ARG A:30, GLN A:31, LYS A:37, LEU A:10, THR A:36, ARG A:126, PHE A:27, PHE A:16, ASN A:15, ASP A:18	Van der Waals
				ASP A:17, VAL A:11, ASP A:12, SER A:13	Conventional Hydrogen Bond
				SER A:34	Carban Hydrogen Bond
				LYS A:14, LYS A:21	Alkyl
2	7AM9	10418553	-9.2	LEU A:292, LYS A:332, MET A: 295, LEU A:361, LYS A:303, ILE A:309 HIS A:362	Van der Waals
				TRP A:336, ASP A:338, ARG A:363, ASP A:293	Conventional Hydrogen Bond
				SER A:335	Carban Hydrogen Bond
				VAL A:239, LEU A:308, LYS A:242, LYS A:296, ILE A: 299	Alkyl
		12309749	-8.8	TRP A:336, ILE A:299, MET A:295, LYS A:296	Van der Waals
				ASP A:293, SER A:335	Conventional Hydrogen Bond
				LEU A:292	Pi-Sigma
				LYS A:332	Pi-Alkyl
		440904	-8.6	TRP A:336	Van der Waals
				ASP A:293	Conventional Hydrogen Bond
				MET A:295	Amide-Pi-Stacked
				LEU A:292, LYS A:296	Pi-Alkyl
3	6T81	12309749	-8.8	LEU A:224, LYS A:225	Van der Waals
		10418553	-8.5	SER A: 99, LYS A:9, LEU A:100, PHE A:231, GLU A:239 VAL A:242, LEU A:240	Van der Waals
				GLN A:103, TYR A :7, ASP A:243	Conventional Hydrogen Bond
				GLY A:8, GLU A:238, LYS A:113, PRO A:13	Carban Hydrogen Bond
				TRP A:245,	Alkyl
				PRO A:247	Pi-Alkyl
		440904	-8.0	ASN A:11	Carban Hydrogen Bond
				GLY A:8	Pi- Donar Hydrogen Bond
				PHE A:231	Pi-Stacked
4	7MBO	10418553	-7.6	ASP A:149, CYS A: 58LYS A:150, HIS A:57, ASP A:194, THR A:213, ALA A;190, GLY A:218, GLY A:216, TRP A:215, SER A:214, ILE A:151, HIS A:40, ARG A:39, LEU A:41	Van der Waals
				LYS A:19, GLY A:193	Conventional Hydrogen Bond
				CYS A:191	Carban Hydrogen Bond
				ARG A:148	Alkyl
		12309749	-7.3	SER A: 195, THR A:213, GLY A:216, GLU A:217, LYS A:192, CYS A:58, CYS A:42, LEU A:41 HIS A:57	Van der Waals
				GLY A:218, GLY A:193	Conventional Hydrogen Bond
				CYS A:191	Carban Hydrogen Bond
				CYS A:219	Pi-Sulfur
				ALA A:190	Amide Pi-Stacked
				LYS A:192	Pi-Alkyl
		440904	-6.8	ASP A:194, SER A:195, THR A:213, CYS A:191, TRP A:215, ALA A:190, GLY A:226, ASP A:189, GLY A:216, GLU A:217, CYS A:219	Van der Waals
				GLY A:218	Conventional Hydrogen Bond
				LYS A:192	Pi-Cation
				LYS A:192	Pi-Alkyl
5	5LHW	12309749	-6.0	GLU A:745, GLN A:741	Van der Waals
				ARG A:742	Pi-Cation
				ALA A:746	Pi-Alkyl
		440904	-5.5	GLN A:732, GLU A:728, GLN A:729, ASP A:730	Van der Waals
				LEU A:733	Pi-Sigma
				LEU A:736	Pi-Alkyl
		10418553	-5.5	LEU A:735, LEU A:736	Van der Waals
				GLN A:732, GLN A:739	Conventional Hydrogen Bond
				ARG A:742	Alkyl

Fig. 2: 3D And 2D Interaction of 3WVM with Tricolorin A, Elymoclavine and Isolysergic acid amid

Fig. 3: 3D and 2D Interaction of 7AM9 with Tricolorin A, Elymoclavine and Isolysergic acid amid

Fig. 4: 3D And 2D Interaction of 6T81 with Tricolorin A, Elymoclavine and Isolysergic acid amid

Fig. 5: 3D And 2D Interaction of 7MBO with Tricolorin A, Elymoclavine and Isolysergic acid amid

Fig. 6: 3D And 2D Interaction of 5LHW with Tricolorin A, Elymoclavine and Isolysergic acid amid

Table 2: ADMET properties of phytochemicals by PkCSM:

Sr. No.	PubChem ID	MW (g/mol)	mLogP	HBA	HBD	MR	TPSA	nRot	Lipinski's Rule(Ro5)	Veber's Rule	Ghose's Rule	Egan's Rule	Muegge's Rule
1	440904	254.33	1.91	2	2	80.34	39.26	1	0	0	0	0	0
2	12309749	267.33	1.39	2	2	82.88	62.12	1	0	0	0	0	0
3	10418553	1023.21	-1.3	21	7	252.56	294.35	17	3	2	3	1	6

Table 3: Drug-Likeness properties of phytochemicals by Swiss ADME:

Sr. No.	PubChem Id	Absorption				Distribution
		Intestinal Absorption (Human)	P-Glycoprotein Substrate	P-Glycoprotein SubstrateI	P-Glycoprotein SubstrateII	VDss (Human)	BBB Permeability	CNS Permeability


		Numeric (% absorbed)	Categorial (Yes/No)	Categorial (Yes/No)	Categorial (Yes/No)	Numeric (log Lkg-1)	Numeric (logBB)	Numeric(logPS)
1	440904	95.017	Yes	No	Yes	1.255	0.228	-1.692
2	12309749	95.526	Yes	No	No	1.131	-0.105	-2.218
3	10418553	23.201	Yes	Yes	No	0.054	-3.111	-3.97

Continue Table 3:

Sr. No.	PubChem Id	Metabolism							Excretion	Toxicity
		Substrate		Inhibitors					TotalClearance	AMES Toxicity
		CYP
		2D6	3A4	1A2	2C19	2C9	2D6	3A4
		Categorial (Yes/No)							Numeric (log mLmin-1kg-1)	Categorial (Yes/No)
1	440904	Yes	Yes	Yes	No	No	Yes	No	1.139	Yes
2	12309749	Yes	Yes	Yes	No	No	No	No	1.01	Yes
3	10418553	No	Yes	No	No	No	No	No	1.17	No

Drug like-ness and ADMET Prediction:

Free online tool SwissADME, created by the Swiss Institute of Bioinformatics, was utilised for drug-likeness assessment and in silico ADME screening. These were the compounds with the highest binding energy scores at this stage of the screening process. Basic physicochemical parameters, including molecular weight (MW), atomic counts, polar surface area (PSA), and molecular refractivity (MR), were computed. To apply drug-likeness candidature, Lipinski, Veber, Ghose, Veber, Egan, and Muegge rules of five (RO5) screening were utilised.

CONCLUSION:

In the context of breast cancer, molecular docking investigations of chemicals from Ipomoea tricolour provide encouraging insights into possible treatment pathways. The anticancer characteristics are just one of many pharmacological actions demonstrated by the bioactive components of Ipomoea tricolour, which include lysergic acid derivatives. Some of these compounds, however, warrant additional investigation due to their ADMET properties. They are considered safe for usage since their BBB and CNS values are low, which means they have limited access to the nervous system.

REFERENCE:

1. Genetics of breast cancer: a topic in evolution. Shiovitz S, Korde LA. Ann Oncol. 2015; 26:1291–1299.

2. Breast Cancer Risk Factors You Can’t Change. [ Jun; 2023]. 2023.

3. Alkabban FM, Ferguson T. Treasure Island, FL: Stat Pearls Publishing; 2023. Breast Cancer.

4. Centers for Disease Control and Prevention. Basic Information About Breast Cancer. [ Jun; 2023]. 2022.

5. Invasive Ductal Carcinoma (IDC): Grade, Symptoms and Diagnosis. [ Jun; 2023]. 2023.

6. Lundqvist A., Andersson E., Ahlberg I., Nilbert M., Gerdtham U. Socioeconomic inequalities in breast cancer incidence and mortality in Europe-a systematic review and meta-analysis. Eur. J. Public Health. 2016; 26: 804–813. Doi: 10.1093/eurpub/ckw070.

7. Azamjah N., Soltan-Zadeh Y., Zayeri F. Global trend of breast cancer mortality rate: A 25-year study. Asian Pac. J. Cancer Prev. 2019; 20: 2015–2020. Doi:10.31557/APJCP.2019.20.7.2015.

8. Breasted JH, editor. The Edwin Smith Surgical papyrus. Chicago, Illinois: The University Chicago Press; 1930. Special edition, 1984.

9. Homer. Iliad. [Translated by WHD Rouse] New York: A Signet Classic. New American Library; 1966. P. 36.

10. Breast cancer. [ Jun; 2023]. 2023.

11. Lyons AS, Petrucelli RJ. Medicine – An illustrated history. New York: Harry N. Abrams Publishers; 1978. Pp. 294–317.

12. Heer E., Harper A., Escandor N., Sung H., McCormack V., Fidler-Benaoudia M.M. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Global Health. 2020; 8(8): e1027– e1037.

13. Anderson B.O., Ilbawi A.M., Fidarova E., Weiderpass E., Stevens L., Abdel-Wahab M., Mikkelsen B. The Global Breast Cancer Initiative: a strategic collaboration to strengthen health care for non-communicable diseases. Lancet Oncol.2021; 22(5): 578–581.

14. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin. 2021; 71:209–249.

15. Ferlay J., Colombet M., Soerjomataram I., Parkin D.M., Piñeros M., Znaor A., et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021; 149:778–789.

16. Global Cancer Observatory: Cancer Today.Khakbazan Z., Taghipour A., Roudsari R.L., Mohammadi E. Help seeking behavior of women with self-discovered breast cancer symptoms: a meta ethnographic synthesis of patient delay. PLoS One. 2014; 9:1–24.

17. Khakbazan Z., Taghipour A., Roudsari R.L., Mohammadi E. Help seeking behavior of women with self-discovered breast cancer symptoms: a meta ethnographic synthesis of patient delay. PLoS One. 2014; 9:1–24.

18. O’Mahony M., McCarthy G., Corcoran P., Hegarty J. Shedding light on women’s help seeking behavior for self-discovered breast symptoms. Eur. J. Oncol. Nurs. 2013; 17:632–639.

19. Current breast cancer risks of hormone replacement therapy in postmenopausal women. Shah NR, Wong T. Expert OpinPharmacother. 2006; 7:2455–2463.

20. Cable JK, Grider MH. Treasure Island, FL: StatPearls Publishing; 2023. Physiology, ProgesteroneEndocrine disruptors from the environment affecting breast cancer. Calaf GM, Ponce-Cusi R, Aguayo F, Mun oz JP, Bleak TC. Oncol Lett. 2020; 20:19–32.

21. Osteoporosis due to hormone imbalance: an overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. Cheng CH, Chen LR, Chen KH. Int J Mol Sci. 2022; 23:1376.

22. Endocrine disruptors from the environment affecting breast cancer. Calaf GM, Ponce-Cusi R, Aguayo F, Mun oz JP, Bleak TC. Oncol Lett. 2020; 20:19–32.

23. The role of progesterone receptors in breast cancer. Li Z, Wei H, Li S, Wu P, MaoX. Drug Des Devel Ther. 2022; 16:305–314.

24. Hormone receptor loss in breast cancer: molecular mechanisms, clinical settings, and therapeutic implications. Zattarin E, Leporati R, Ligorio F, Lobefaro R, Vingiani A, Pruneri G, Vernieri C. Cells. 2020; 9:2644.

25. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Dunnwald LK, Rossing MA, Li CI. Breast Cancer Res. 2007; 9:0.

26. Targeted therapies in breast cancer: new challenges to fight against resistance. Masoud V, Page s G. World J Clin Oncol. 2017; 8:120–134.

27. Use of hormone replacement therapy and risk of breast cancer: nested casecontrol studies using the QResearch and CPRD databases. Vinogradova Y, Coupland C, Hippisley-Cox J. BMJ. 2020; 371:0.

28. Bonofiglio D., Giordano C., De Amicis F., Lanzino M., Ando S. Natural products as promising anti-tumoral agents in breast cancer: Mechanisms of action and molecular targets. Mini Rev. Med. Chem. 2016; 16:596–604. Doi:10.2174/1389557515666150709110959.

Received on 01.07.2024 Revised on 11.12.2024

Accepted on 12.04.2025 Published on 03.05.2025

Available online from May 05, 2025

Asian J. Pharm. Res. 2025; 15(2):97-103.

DOI: 10.52711/2231-5691.2025.00016

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.