MOLECULAR DOCKING ANALYSIS OF COMPARISON BETWEEN INDOLE ALKALOID COMPOUNDS FROM CATHARANTHUS ROSEUS WITH THE TARGETS FOR BREAST CANCER

MOLECULAR DOCKING ANALYSIS OF COMPARISON BETWEEN INDOLE ALKALOID COMPOUNDS FROM CATHARANTHUS ROSEUS WITH THE TARGETS FOR BREAST CANCER

S. Aishwariya, M. Viji, C. Ireen, P. Vijayalakshmi, S. Indu and M. Rajalakshmi *

Department of Zoology, Holy Cross College (Autonomous), Tiruchirappalli, Tamil Nadu, India.

ABSTRACT: Endocrine-disrupting chemicals are environmental pollutants that have been associated with a wide range of diseases, including breast cancer, the most prevalent cancer in women worldwide, according to the WHO. Among the different cancers affecting the female population, breast cancer has the highest incidence and mortality rate. The incidence of breast cancer is 100 times higher in women than in men. The incidence of breast cancer is alarmingly high, so the need for a novel approach with fewer side effects is currently needed to improve the quality of life of the patients. Catharanthus roseus is a plant species belonging to the Apocynaceae family that is used worldwide in phytotherapy. The indolic alkaloids (vincristine and vinblastine) isolated from C. roseus are approved and used in clinical trials. The interest of the study lies in the comparison of indole alkaloids (vincristine and vinblastine) against breast cancer targets through in-silico studies. The work of the study lies upon downloading target and ligand. The targets that are associated with breast cancer were downloaded from PDB. The ligands (vincristine and vinblastine) were downloaded from PubChem. To compare and calculate ADMET properties and drug-likeliness for vincristine, vinblastine, and the reference drug (paclitaxel), Molecular interaction of cancer targets with vincristine and vinblastine. Based on the results, vinblastine has a greater and better number of binding affinities towards breast cancer proteins. From the analysis, it says that vinblastine has a better potential to treat breast cancer.

Keywords: Breast cancer, Vinblastine, Vincristine, ADMET, Molecular Docking

INTRODUCTION: Cancer is one of the deadliest diseases, which includes abnormal cell growth. The spread may occur directly, via the bloodstream, or via the lymphatic system ¹. Numerous organs can be affected by cancer, and each type of cancer has specific traits.

Among the different cancers affecting the female population, breast cancer has the highest incidence and mortality rate. The incidence of breast cancer is 100 times higher in women than in men. According to previous studies, this type of cancer caused 5,70,000 deaths in 2015 ².

Throughout the world, 25% of women are diagnosed with this type of cancer. 30% of new cancer cases among women were reported as breast cancer in America in 2017 ³. In 2004, according to the global cancer burden, the death rate was 8.8 million, and the estimation can increase with an increase in population. The death rate is expected to increase by 10-fold in the year 2030, and the incidence may increase to 26.4 million ⁴. Oncogene and anti-oncogene mutations and abnormal amplification play important roles in the development and spread of tumours. Two well-known anti-oncogenes for the risk of breast cancer are BRCA1 and BRCA2. The BRCA genes are found on chromosomes 13q12 and 17q21, respectively. Dysregulation of the cell cycle checkpoint, abnormal centrosome duplication, and genetic instability are due to a deficiency of BRAC 1 ⁵. High-grade invasive ductal carcinomas with a luminal phenotype are more prevalent in breast cancers linked to BRCA2 ⁶.

Overexpression of human epidermal growth factor receptor 2 (HER2), an oncogene located on 17q21, was observed in 20% of primary breast cancer ⁷. Overexpression of EGFR is found in more than 30% of cases of inflammatory breast cancer (IBC), a very aggressive subtype of breast cancer ⁸. Ageing is one of the important risk factors. The study reported that in America, the age of the women associated with breast cancer is 40-60. Reproductive factors such as early menarche, late menopause, late age at first pregnancy, and low parity can increase the breast cancer risk ⁹.

Screening, chemoprevention, biological prevention, and immunotherapy are some measures that facilitate the treatment of breast cancer. Though a number of treatments are available, the incidence of breast cancer is alarmingly high, so the need for a novel approach with fewer side effects is currently needed to improve the quality of life of the patients.

According to previous studies phytotherapy can also treat cancer. Based on the study, one such plant is Catharanthus roseus, a perennial tropical plantbelonging to the Apocynaceae family. The plant is widely distributed in areas like America, Africa, Australia, the southern part of Europe, the Pacific Ocean islands, and India. The plant is used as remedies against diseases like diabetes, diuretics, and cough ¹⁰. The plant contains more than 180 various indole alkaloids used in worldwide traditional medicine. Alkaloids have been shown to have numerous therapeutic uses that are extremely beneficial to people. Alkaloids have been shown to have anti-inflammatory ^11–12, antiviral ¹³, antimicrobial/bacterial ¹⁴, and an impact on neurodegenerative disorders and central nervous system (CNS) disease ¹⁵. Alkaloids are highly valued for their anticancer properties in addition to these ¹⁶. The alkaloids pericalline, perivine, leurosivine, perividine, and vindoline show antiviral activity against vaccinia and polio type III viruses. The plant extract of C. roseus has anti-virus activity against dengue type II virus ¹⁷, anti-bacterial activity towards Salmonella typhi, and Shigella boydii ¹⁸, and it also exhibited predominant antifungal activity against Rigidoporus microporus, Ganoderma philippii, and Phellinus noxius ¹⁹.

The two main vinca alkaloids used for cancer therapy against leukaemia, Hodgkin’s disease and solid tumours are vincristine and vinblastine ²⁰. The indole alkaloid vincristine is approved to treat acute leukaemia, neuroblastoma, Wilm’s tumour, and refractory autoimmune thrombocytopenia. Another compound isolated from c.roseus is a microtubule destabilizer (vinblastine). According to previous studies, vinblastine, when combined with mitomycin and Taxol, is used as the first line of treatment in advanced ovarian and breast cancer, non-small cell lung cancer (NSCLC) ²¹, and Kaposi's sarcoma ²².

Vinblastine is commonly used to treat breast cancer, ovarian cancer, malignant lymphoma, Hodgkin’s disease, and choriocarcinoma ²³. The current work is designed to analyse the pharmacokinetic properties and in silico analysis of indole alkaloids (vincristine and vinblastine) with breast cancer targets to determine which compounds have higher efficacy.

METHODOLOGY:

Target Preparation: The targets were downloaded from the PDB database in PDB format. The targets used are BAK (PDB ID: 2YV6), BAX (PDB ID: 2K7W), BCL-2 ( PDB ID: 1G5M), BCL-XL (PDB ID:1G5J), Caspase-3 (PDB ID: 1GFW), Caspase-6 (PDB ID :2WDP), Caspase-8(PDB ID: 5JQE), Caspase-9 (PDB ID:  1NW9), P52(PDB ID :1A3Q), P65 (PDB ID:1NFI), P100 (3DO7), CAT (PDB ID:1QQW), SOD ( PDB ID: 1SPD), GPX2 ( PDB ID:2HE3), CDK-4 (PDB ID: 3G33), CDK-6 (PDB ID: 1G3N), Cyclid-D1 (PDB ID:2W99), Cyclidin-D3 (PDB ID:3G33), CDK-6 ( PDB ID :1G3N), P21 (PDB ID :1AXC), P27 (PDB ID:1JSU), EGFR (1M17) and HER 2 (3PP0). Thus, targets were prepared by removing any heteroatoms, water molecules chains, and other associated ligand groups using Discovery Studio Biovia visualiser client.

Ligand Preparation: Before starting a virtual screening, all the chemical structures for a certain pharmacological target must be gathered. Many compound databases have been created recently that store a variety of chemical and biological data in addition to the structure of the compound molecules. One such database is PubChem. By using the canonical smiles, the 2D structure of the ligands (active compounds and reference drugs) was generated using ACD/labs Chemsketch. Paclitaxel is used as a reference drug in this study.

Pharmacokinetics Properties: The pharmacokinetic properties like Lipinski rule of five and ADMET were obtained through pkCSM online server.

Molecular Docking: PyRx version 0.8 is used to prepare all protein and ligand files for docking and to generate docking parameter input files. All PDB files for proteins and ligands were converted into PDBQT format using PyRx. The ligands were inserted using an open babel. The Universal Force Field (UFF) served as the energy reduction parameter, and the optimization algorithm used conjugate gradient descent.

As a result, the stronger binding capacity is demonstrated by the lower binding energy score, and the results were downloaded in PDB and CSV file formats. The visualization process is done by the Biovia 2021 R2 client software package, which analyzes the H-bond interaction and other intermolecular interactions between the target and the receptors.

RESULTS AND DISCUSSION: Due to the high incidence of breast cancer worldwide, it is a cause for concern on a global scale. The increasing upsurge in breast cancer cases highlights the need for multi-level disease care. Effective management should begin at the outset with strict cancer screening programmes or a cancer registry, followed by efficient diagnostic and therapeutic approaches. Breast cancer is extremely variable in terms of morphology and at the molecular level, necessitating several therapy modalities depending on the molecular subtype. Clinical prognoses for breast cancer patients vary depending on their subtype. The enhanced molecular testing that will aid in early detection and improved survival is highlighted by the heterogeneity of breast cancer. Even though there are various treatment are available for breast cancer, they are cost effective and each of them have their own side effect. As a result of the search to reduce the risk of those treatment and to manage breast cancer, the Food and Drug Administration (FDA) has approved over 60% of antineoplastic medications that come from natural sources (e.g., vincristine, topotecan, or paclitaxel). These medications can be used as lead compounds with minor modifications or in their monomeric form ²⁴.

Phytotherapy is a booming filed that comprisesa number of phytocompound that are used against various kinds of disease. One such plant is Catharanthus roseus which is an herbal plant widely used in traditional medicine. Various compounds were isolated from this plant, the two most important compound are vinblastine and vincristine. Vinblastine is used to treat several cancers, including Kaposi's sarcoma, neuroblastoma, Hodgkin's and non-Hodgkins's lymphomas, mycosis fungoides, and testicular cancer. Vinblastine is considered to suppress mitosis at metaphase through its interaction with tubulin, which accounts for the majority of its anticancer effect. Vinblastine causes the microtubule to crystallise and causes mitotic arrest or cell death when it attaches to the mitotic spindle's microtubular proteins ²⁵.

On other hand vincristine, it is sold under numerous brand names, many of which have various formulations, such as Vincasar and Marqibo (liposomal injection). Acute leukemia, malignant lymphoma, Hodgkin's disease, acute erythremia, and acute panmyelosis are among the conditions for which vincristine is prescribed. Because of its distinctive clinical toxicity (neuropathy) and absence of considerable bone-marrow suppression (at acceptable doses), vincristine sulphate is frequently used as a component of polychemotherapy ²⁶. The structures for reference drug, and indole alkaloid compounds is obtained through chemsketch Fig. 1.

Structure of Ligands and Reference Drug:

FIG. 1: 2D STRUCTURE OF (A) PACLITAXEL (B) VINCRISTINE (C) VINBLASTINE WERE DRAWN THROUGH ACD/LABSCHEMSKETCH

Lipinski Rule of Five and Pharmacokinetics Properties: The active compounds and reference drug were subjected to checking whether they follow the “Lipinski Rule of Five” through the pkCSM tool Table 1. Lipinski himself stated that his “Rule of Five” is not applicable to natural products. Both (vinblastine and vincristine) were naturally obtained; the molecular weight and hydrogen donor-acceptor of these compounds do not come under the Lipinski rule of 5. But it follows the log p-value, rotatable bond, and hydrogen bond donor. The reference drug, paclitaxel, is a synthetic drug that follows the rule. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the ligands were obtained through the pkCSM tools Table 2. The indole alkaloid compounds vincristine and vinblastine exhibited good absorption values. In distribution properties, VDss is used to analyze the distribution of drugs in tissue rather than plasma. The values of the compounds are >0.45, whereas vincristine and vinblastine have (1.654 and 1.582) values, respectively, indicating a small amount of the compound distributed in tissue. BBB and CNS parameters are quite important to know whether a drug has the ability to cross the brain or not. The compounds have values less or equal to -1 and -3 in the BBB and CNS, respectively, which are poorly distributed in the brain and could not penetrate the CNS. In metabolism, the two main isomers (CYP2D6 and CYP3A4) of CYP450 play a crucial role in drug metabolism. The compounds act as substrates and inhibitors for CYP3A4, but they don’t act as substrates or inhibitors for CYP2D6. In excretion, the value of total clearance is low, indicating the high bioavailability of the compound, and the compounds are not substrates for renal OCT2. In terms of toxicity properties, the compounds are not inhibitors of hERG, which does not cause QT prolongation, and they don’t possess hepatotoxicity, which could not lead to liver injury.

TABLE 1: LIPINSKI RULE OF 5 FOR THE LIGANDS PACLITAXEL, VINCRISTINE AND VINBLASTINE

TABLE 2: ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION AND TOXICITY PROPERTIES OF PACLITAXEL, VINCRISTINE AND VINBLASTINE

Moleucular Interactions: In order to anticipate the level of activity or binding affinity of the interaction between the receptor and the ligand, a computer technique called molecular docking first determines the preferred location of a molecule (the ligand) in relation to a second molecule (the receptor) when the two molecules join to form a stable complex. The interactions were run for three ligands (paclitaxel, vincristine, and vinblastine) against twenty-three targets associated with breast cancer. The molecular docking was run through Pyrx software and visualised through Bio via the 2021 visualizer client. According to Bhatnagar, the indole alkaloid compound vinblastine has better binding affinity with α/β-tubulin than vincristine ²⁷.

Even though previous studies say that vinblastine and its derivative, vindesine, are often more effective than vincristine and vinepidine in reducing cell proliferation in culture, the purpose of the paper is to compare which indole alkaloid compound has the highest efficacy against the breast cancer protein through computational analysis. The interactions through docking between targets and ligands were shown below Fig. 2–16, and the binding affinity and polar interactions between the targets and reference drug were listed below Table 3. In the apoptotic marker, the compound vinblastine shows better binding affinity towards BCL-XL (-7.4), and it shows double H-bond interaction (Arg-104, Asn-140). When vinblastine docks with cell cycle proteins, it shows high binding affinity for CDK4 (-7.5) and a single H-bond interaction (Gln-193). For other proteins like NFKβ, oxidative stress, and the breast cancer gene, the compound vinblastine shows a good number of binding affinities towards P100 (-7.7), CAT (-8.5), and HER-2 (-7.5). While vincristine shows binding affinity as (-7.2, -8.9, and -7.1), When comparing the H-bond interactions, vinblastine shows a single H-bond interaction (Gln-157) for P100; for oxidative stress proteins, it shows two H-bond interactions (Asn-338, Arg-382) towards CAT; and finally, for HER-2, it shows four H-bond interactions (Ile-886, Arg-756, Phe-731, Gly-732). Vincristine shows a single H-bond interaction with CDK-4 (Arg-168) for p100 and BCL-Xl, it does not show any H-bond interaction; for the oxidative stress protein CAT, it shows four H-bond interactions (Asn-338, Glu-420, Gln-415, Asn385); and for HER2, it shows a single H-bond interaction (Ala-698).

Thus, as a result of the comparison between vinblastine and vincristine, the compound vinblastine has better potential to treat breast cancer. In order to anticipate the level of activity or binding affinity of the interaction between the receptor and the ligand, a computer technique called molecular docking first determines the preferred location of a molecule (the ligand) in relation to a second molecule (the receptor) when the two molecules join to form a stable complex. The interactions were run for three ligands (paclitaxel, vincristine and vinblastine) against twenty-three targets -associated with breast cancer. The molecular docking was run through Pyrx software and visualized through Bio via 2021 visualizer client type. According to Bhatnagar, the indole alkaloid compound vinblastine has better binding affinity with α/β-tubulin than vincristine ²⁷. Even though previous studies says that Vinblastine and its derivative, vindesine, were often more effective than vincristine and vinepidine in reducing cell proliferation in culture. The work of the paper is to compare which indole alkaloid compound has highest efficacy towards the breast cancer protein through computational analysis. The interactions through docking between targets and ligands were shown below Fig. 2 to Fig. 16 and the binding affinity and polar interactions between for the targets and reference drug were listed below Table 3. In apoptotic marker the compound vinblastine shows better binding affinity towards BCL-XL (-7.4), and it shows double H- bond interaction (Arg-104, Asn-140). When vinblastine docked with cell cycle proteins it shows high binding affinity for CDK4 (-7.5) and shows single H-bond interaction (Gln-193). For other proteins like NFKβ, Oxidative stress and Breast cancer gene the compound vinblastine shows good number of binding affinities towards P100(-7.7), CAT (-8.5), and HER-2(-7.5). While vincristine shows binding affinity as (-7.2, -8.9, and –7.1). When comparing the H-bond interaction, vinblastine shows single H- bond interaction (Gln-157) for P100, for oxidative stress protein it shows two H- bond interaction (Asn-338, Arg-382) towards CAT and finally for HER-2it shows four H- bond interaction (Ile-886, Arg-756, Phe-731, Gly-732). Vincristine shows single H-bond interaction towards CDK-4 ((Arg-168) for p100 and BCL-Xl it does shown any H-bond interaction, for oxidative stress protein- CAT it shows four H-bond interaction (Asn-338, Glu-420, Gln-415, Asn385) and for HER2 it shows single H-bond interaction (Ala-698). Thus, as a result of comparison between vinblastine and vincristine the compound vinblastine has better potential to treat breast cancer.

Molecular Interaction of Brest Cancer Targets with Paclitaxel:

FIG. 2: MOLECULAR INTERACTIONS OF (A) P52, (B) P65, (C) P100 NFΚB   PROTEINS ARE DOCKED WITH PACLITAXEL

FIG. 3: MOLECULAR INTERACTIONS OF (A) CAT, (B) SOD, (C) GPX2 OXIDATIVE STRESS, PROTEINS ARE DOCKED WITH PACLITAXEL

FIG. 4: MOLECULAR INTERACTIONS OF (A) CDK-4, (B) CDK-6, (C) CYCLIN D1, (D) P21, (E) P27 CELL CYCLE PROTEINS ARE DOCKED WITH PACLITAXEL

FIG. 5: MOLECULAR INTERACTIONS OF (A) BCL-XL, (B) BCL-2, (C) BAX, (D) BAK, (E) CASPASE -3, (F) CASPASE-9, (G) CASPASE-6, (H) CASPASE-8, APOPTOTIC PROTEINS DOCKED WITH PACLITAXEL

FIG. 6: MOLECULAR INTERACTIONS OF (A) EGFR, (B) HER 2 ARE DOCKED WITH PACLITAXEL

Molecular Interaction of Brest Cancer Targets with Vincristine:

FIG. 7: MOLECULAR INTERACTIONS OF (A) P52, (B) P65, (C) P100 NFΚB   PROTEINS ARE DOCKED WITH VINCRISTINE

FIG. 8: MOLECULAR INTERACTIONS OF (A) CAT, (B) SOD, (C) GPX2 OXIDATIVE STRESS, PROTEINS ARE DOCKED WITH VINCRISTINE

FIG. 9: MOLECULAR INTERACTIONS OF (A) CDK-4, (B) CDK-6, (C) CYCLIN D1, (D) P21, (E) P27 CELL CYCLE PROTEINS ARE DOCKED WITH VINCRISTINE

FIG. 10: MOLECULAR INTERACTIONS OF (A) BCL-XL, (B) BCL-2, (C) BAX, (D) BAK, (E) CASPASE -3, (F) CASPASE-9, (G) CASPASE-6, (H) CASPASE-8, APOPTOTIC PROTEINS DOCKED WITH-VINCRISTINE

FIG. 11: MOLECULAR INTERACTIONS OF (A) HER 2 (B) EGFR ARE DOCKED WITH VINCRISTINE

Molecular Interaction of Brest Cancer Targets with Vinblastine:

FIG. 12: MOLECULAR INTERACTION OF (A) P52, (B) P65, (C) P100 NFKB PROTEINS ARE DOCKED WITH VINBLASTINE

FIG. 13: MOLECULAR INTERACTION OF (A) CAT, (B) SOD, (C) GPX2 OXIDATIVE STRESS PROTEINS ARE DOCKED WITH VINBLASTINE

FIG. 14: MOLECULAR INTERACTIONS OF (A) CDK-4, (B)CDK-6, (C) CYCLIN D1, (D) P21, (E) P27 CELL CYCLE PROTEINS ARE DOCKED WITH VINBLASTINE

FIG. 15: MOLECULAR INTERACTIONS OF (A) BCL-XL, (B) BCL-2, (C) BAX, (D) BAK, (E) CASPASE -3, (F) CASPASE-9, (G) CASPASE-6, (H) CASPASE-8, APOPTOTIC PROTEINS DOCKED WITH VINBLASTINE

FIG. 16: MOLECULAR INTERACTIONS OF (A) HER 2 (B) EGFR ARE DOCKED WITH VINBLASTINE

TABLE 3: BINDING AFIINITIES AND H-BOND INTERACTION FOR TARGETS AND REFERENCE DRUG

CONCLUSION: On the basis of comparison between the compound’s vinblastine has greater and good number of binding affinities towards breast cancer proteins. So, from the analysis it says that vinblastine has a better potential to treat against breast cancer. Subsequent exploitation of the compound through experimental studies in the future will provide insights into developing vinblastine into effective drug moieties.

ACKNOWLEDGMENT: I acknowledge the infrastructure facility of DBT-BIF Centre at Holy Cross College for helping me in carrying out my work.

CONFLICTS OF INTEREST: There are no conflicts of interest.

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    How to cite this article:

    Aishwariya S, Viji M, Ireen C, Vijayalakshmi P, Indu S and Rajalakshmi M: Molecular docking analysis of comparison between indole alkaloid compounds from Catharanthus roseus with the targets for breast cancer. Int J Pharm Sci & Res 2024; 15(5): 1466-77. doi: 10.13040/IJPSR.0975-8232.15(5).1466-77.

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