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. 2024 Jun 8;12(1):53. doi: 10.1007/s40203-024-00227-y

Phytochemical analysis, physicochemical, pharmacokinetic properties and molecular docking studies of bioactive compounds in Ottelia alismoides (L.) pers. Against breast cancer proteins

Sathish Muthukrishnan 1,✉, Suriya Sekar 1, Chamundeeswari Raman 1, Jeevan Pandiyan 1, Jansirani Ponnaiah 2
PMCID: PMC11162403  PMID: 38860144

Abstract

Plants provide compounds that can be used to treat diseases, and in silico methods help to expedite drug discovery while reducing costs. This study explored the phytochemical profile of methanol extract of O. alismoides using GC-MS to identify potential bioactive compounds. Autodock 4.2.6. was employed for molecular docking evaluation of the efficacy of these identified compounds against Estrogen Receptor Alpha (ERα), Human Epidermal Growth Factor Receptor 2 (HER2), and Epidermal Growth Factor Receptor (EGFR), proteins. Additionally, the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the compounds were predicted using the SwissADME online tool. The preliminary phytochemical analysis revealed the presence of alkaloids, carbohydrates, glycosides, and steroids. During the GC-MS analysis, seven compounds were identified, and drug-likeness prediction of these compounds showed good pharmacokinetic properties having high gastrointestinal absorption, and orally bioavailable. The molecular docking studies exhibited promising binding affinities of bioactive compounds against all target proteins. Specifically, the compounds Tricyclo[5.2.1.0(2,6)]decan-10-ol and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide demonstrated the highest binding affinities with the ERα (-6.3 and − 6.0 k/cal), HER2 (-5.6 and − 6.1 k/cal), and EGFR (-5.4 and − 5.4 k/cal), respectively. These findings suggest the potential of O. alismoides as a source for developing new cancer therapeutics. The study highlights the effectiveness of in silico approaches for accelerating drug discovery from natural sources and paves the way for further exploration of these promising compounds.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40203-024-00227-y.

Keywords: Molecular Docking, Ottelia alismoides, Palmitic acid, Ethyl palmitate and drug-likeness properties

Introduction

Cancer is defined by the unchecked growth and division of cells, disrupting the usual cell division process (Ur Rashid et al. 2019). It’s among the most significant health challenges we confront. Moreover, cancer-related fatalities are increasing, expected to surpass cardiovascular disease deaths soon (Al-Warhi et al. 2020). The WHO reported 19.3 million new cancer cases and 10 million deaths in 2020. It is expected to reach 30.2 million new cases and 16.3 million fatalities by 2040 (Globocan, 2020). Cancer cells can be invasive, aggressive, and metastatic, spreading to various organs. Breast cancer is a highly heterogeneous disease that disrupts the normal function of mammary epithelial cells. It is the most common non-skin cancer and a leading cause of cancer-related death in women worldwide (Yedjou et al. 2019). Globally, it affects more than one in ten women (Torre et al., 2012). Excessive estrogen production is considered a major contributor to breast cancer. The estrogen receptor (ER), a nuclear receptor activated by binding to estrogen (17β-estradiol), plays a crucial role. Humans naturally express ER-α and ER-β, which regulate various physiological processes like cell growth and differentiation. Notably, ER-α is highly expressed in the mammary gland and uterus (Rafeeq 2022). HER2, on the other hand, belongs to a superfamily of human peptide ligands called epidermal growth factor receptors (EGFR) that includes HER1, HER2, HER3, and HER4. Notably, EGFR and HER2 are considered some of the most promising therapeutic targets for cancer treatment (Sait et al. 2020). Worldwide, intense research aims to create drugs that accurately target and eradicate cancer cells. Often, non-toxic plant extracts are combined with chemotherapy treatments to reduce the dose and side effects (Al-Zahrani et al. 2022). Medicinal plant compounds can be used to treat various illnesses and support chemotherapy side effect reduction (Hosseinzadeh et al. 2015; Mintah et al. 2019; Sathish et al. 2024). Plants have multifaceted roles. They’re key sources of essential nutrients and abound with health-promoting bioactive components that fight numerous diseases (Liu, 2003). These components, including lipids, phytochemicals, and pharmaceuticals, are utilized in the food, medicine, and beauty sectors. In places like India, incredibly under-resourced areas, plant-based traditional medicines are integral to healthcare due to their precise phytochemical components (Velmurugan and Anand 2017; Sathish et al. 2024). Particularly in India’s rural northeast, diverse plants and local socio-economic conditions have fostered reliance on traditional medicine. Plants from this region, abundant in bioactive compounds, exhibit antimicrobial, anticancer, anti-inflammatory, and antioxidant properties. Traditional remedies often use extracts rich in phytochemicals for chronic and infectious conditions (Sahoo and Manchikant, 2013).

Ottelia alismoides, or Duck lettuce, is adapted to saline and freshwater aquatic environments. These plants have evolved traits for submerged or floating life (Hutchinson GE, 1975; Cook CDK, 1974). Many countries spanning tropical and subtropical Asia and Australia have reported its presence, encompassing a broad geographical expanse. Within India, the plant can be located in diverse aquatic environments like tanks, ponds, streams, and ditches (Pullaiah et al. 2003). This plant stands out prominently in various locations, such as the aquatic herb situated in the rear waters of Madhuban Dam near Dudhani, the Silvassa region, Kamrup district in Assam, Pondicherry, Ariyalur, Kunnathur tank in Madurai district, Tamil Nadu (Sumithira et al. 2017), and even along the Vellaru River in Pudukkottai District. Traditionally, O. alismoides has been a remedy for diseases like cancer, tuberculosis, and diabetes. Yet, treating certain cancers, especially lung and skin, is challenging due to rapid growth and drug resistance (Das et al. 2023). While many plants have bioactive secondary metabolites, few have been intensely researched as key bioactive sources. Hence, creating effective screening techniques for new compounds is crucial (Keskes et al. 2017). Advances in extraction processes have produced potent medicines (Yadav et al. 2017). Gas chromatography-mass spectrometry (GC-MS) is typical for pinpointing plants’ bioactive elements (Satapute et al. 2019; Fan et al. 2018). Razack et al. (2015) vouched for GC-MS’s efficacy in detecting compounds in plant extracts. With technological progress, state-of-the-art tools aid drug discovery, screening medicinal plants for potential drugs (Sliwoski et al. 2014). Computational prediction is vital in drug development to comprehend drug features, promoting pharmaceutical advancements (Loza-Mejia et al. 2018). Among cost-effective strategies, molecular docking provides crucial insights into drug-protein interactions (Lee and Kim, 2019; Bharathi et al. 2014). This research examines the limited studies on O. alismoides and its bioactive components, focusing on identifying these compounds and conducting in silico molecular docking studies for anticancer potential. These in silico results can guide lab experiments in vitro, in vivo, or ex vivo.

Materials and methods

Collection and preparation of plant extract

The plant material chosen for this study was whole plant parts of Ottelia alismoides (L.) Pers., a member of the Hydrocharitaceae family. It was gathered from the Vellaru River in Sivapuram, Pudukkottai district, Tamil Nadu, India, in December 2022. The identification and confirmation of the plant were conducted by the PG and Research Department of Botany at J.J. College of Arts and Science (Autonomous), Pudukkottai, Tamil Nadu, India. The collected plant materials underwent a thorough washing with tap water to remove sediment particles. To prepare the methanolic extract, the plant materials were again washed meticulously and then spread out on blotting paper in the shade at room temperature for drying. Subsequently, the shade-dried samples were finely powdered using a tissue blender. A total of 30 g of powdered samples were placed in a Soxhlet apparatus and separately extracted with methanol for a duration of 8 h (Iniya et al. 2017).

Preliminary phytochemical analysis of O. alismoides

The methanolic extract of O. alismoides underwent qualitative phytochemical prescreening using established protocols (Tiwari et al. 2011). To prepare the standard solution, 100 mg of plant extract was dissolved in 10 mL of methanol. Subsequently, these solutions were screened to detect the presence of various phytochemicals, namely Tannins, Alkaloids, Flavonoids, Proteins, Carbohydrates, Glycosides, Saponins, Triterpenoids, Steroids, and Starch.

Gas chromatography and mass spectrometry (GC–MS) analysis of O. alismoides methanolic extract

Using a Thermo Scientific Co. GC-MS system (model Thermo GC-TRACE ultra, version 5.0, Thermo MsDsq II), the phytoconstituent of O. alismoides extract was identified. A 100 µl methanolic extract of O. alismoides was dissolved in 1 ml of solvent, mixed, and filtered using a membrane filter. Chromatography was conducted on a DB 35-MS capillary standard non-polar column with dimensions of 15 m length, 0.25 μm film thickness, and 0.25 mm inner diameter. Helium was the carrier gas at a 1.0 ml/min flow rate. The sample injection volume was 1 µl in the split mode at a ratio of 1:10. The injector temperature was set at 240 ºC, while the transfer line temperature was maintained at 280°C. The instrument’s column temperature started at 50ºC for 2 min and then increased at 5ºC per minute until it reached 260ºC, where it was held for 10 min. The instrument operated at 70 eV, and the sample underwent scanning within a mass spectral range of 42–350 (m/z). Subsequently, the obtained GC-MS compound peaks were analyzed using NIST (Fig. 1).

Fig. 1.

Fig. 1

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GC–MS chromatogram of the methanol extract of O. alismoides

ADMET analysis

Identified bioactive compounds from GC-MS analysis of O. alismoides were evaluated the Absorption, Distribution, Metabolites, Excretion and Toxicity (ADMET) properties using a free web tool of SwissADME (http://www.swissadme.ch) (Hodgson 2001; Daina et al. 2017).

Molecular Docking studies

The three-dimensional (3D) structure of identified bioactive compounds (Fig. 2) in O. alismoides were retrieved from the PubChem database and then converted into Mol, PDBQT, and PDB formats utilizing the Open Babel software (Neema et al. 2015). Structure-based molecular docking was performed with various cancer proteins (Fig. 3), such as the X-ray crystal structure of the three molecular targets Estrogen Receptor Alpha (PDB ID: 3ERT) (Raju et al. 2021), Epidermal Growth Factor Receptor (PDB ID: 2J6M) (Acharya et al. 2019), and Human Epidermal Growth Factor Receptor 2(PDB ID: 1N8Z) (Megantara et al. 2022). These proteins were sourced from the Protein Data Bank of the Research Collaboratory for Structural Bioinformatics and were converted to pdbqt coordinates using Auto Dock Tools. Before transforming the protein for auto docking, the protein was purged of water molecules and inhibitors. Polar hydrogen atoms were added using Auto Dock Tools, Kollman charges were designated, and the altered enzyme structure was supplied as an input for the Autogrid program. Each docking system underwent 150 Lamarckian genetic algorithm iterations during the Autodock search. The optimal pose for each ligand was selected for further investigation of its interactions with target proteins. The results were visualized and interpreted using Discovery Studio 4.0 Client (Neema et al. 2015).

Fig. 2.

Fig. 2

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3D Structure of Bioactive compounds in O. alismoides (a) 3,5-Di-tert-butylphenol; (b) 2-Decynoic acid; (c) Tricyclo[5.2.1.0 (2,6)]decan-10-ol; (d) 4-Nonyne; (e) Palmitic Acid; (f) Ethyl palmitate and (g) 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide

Fig. 3.

Fig. 3

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3D Structure of Target Proteins (a) Estrogen Receptor Alpha (PDB ID: 3ERT), (b) Epidermal Growth Factor, (b) Human Epidermal Growth Factor Receptor 2

Results

Preliminary phytochemical analysis of O. alismoides

The preliminary phytochemical analysis of the methanol extract from O. alismoides aerial plant parts revealed the presence of multiple bioactive compounds such as, tannins, alkaloids, carbohydrates, glycosides, and steroids (Table 1).

Table 1.

Preliminary Phytochemical Screening of Methanol Extract of O. alismoides

S.No Phytochemical Methanol Extract
1. Tannins +
2. Alkaloids +
3. Flavonoids -
4. Proteins -
5. Carbohydrates -
6. Glycosides -
7. Saponins -
8. Triterpenoids +
9. Steroids -
10. Starch -
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Present (+) Absent (-)

GC-MS analysis of O. alismoides

The methanol extract of O. alismoides underwent further analysis via GC-MS to discern its phytochemical constituents. The chromatograph produced seven prominent peaks, indicating the presence of seven compounds such as 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0(2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide Acid. Table 2; Fig. 1 represent the chromatogram of the extract, demonstrating various compounds, retention times (RT), molecular formula (MF), molecular weights (MW), and respective concentrations (%).

Table 2.

GC-MS Analysis of Methanol extract of O. alismoides

P. No Peak Name Compound Name M.W M. F Area % RT
1. Phenol, 3,5-bis(1,1-dimethylethyl)- 3,5-Di-tert-butylphenol 206.32 C14H22O 2.53 6.881
2. 2-Decanynoic acid 2-Decynoic acid 168.23 C10H16O2 9.79 9.812
3. Tricyclo[5.2.1.0 (2,6)]decan-10-ol Tricyclo[5.2.1.0 (2,6)]decan-10-ol 152.23 C10H16O 5.55 10.133
4. 4-Nonyne 4-Nonyne 124.22 C9H16 5.43 11.712
5. n-Hexadecanoic acid Palmitic Acid 256.42 C16H32O2 54.98 11.987
6. Hexadecanoic acid, ethyl ester Ethyl palmitate 284.5 C18H36O2 14.53 12.478
7. 7-Oxabicyclo[4.1.0]heptane, 1,5- 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide 244.5 C7H8Cl3NO2 7.19 14.842
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Peak No (P. No); Molecular Weight (M.W) Molecular Formula (M.F); Retention Time (R.T)

Physicochemical and pharmacokinetic properties of Phytocompounds from O. alismoides

The evaluation encompassed the ADMET attributes of the interacting bioactive compounds from the methanolic extract of O. alismoides. These identified compounds possessed a molecular weight that did not exceed 500 g/mol. Seven compounds displayed X Log P3 values from 0.90 to 4.67, while their TPSA values were confined to 0.00 to 55.62. A variation between − 2.06 and − 5.51 was observed regarding Log S values. Fraction Csp3 values, on the other hand, showcased a spectrum from 0.57 to 1.00. Rotatable bonds, ranging from 1 to 16, were characteristic of all compounds (Table 3). Prominent among the interacting phytochemicals were those that conformed to Lipinski’s rule of five, indicating favourable interactions. Notably, a substantial portion of these compounds exhibited the capacity to traverse the blood-brain barrier (BBB) effectively and displayed high levels of intestinal absorption. Within the analyzed phytochemicals, a bioavailability score of 0.55 was generally noted. However, 2-Decynoic acid and Palmitic Acid stood out with a higher score of 0.85 (Table 4). Certain compounds, such as 2-Decynoic acid, Tricyclo[5.2.1.0(2,6)]decan-10-ol, 4-Nonyne, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptanecarboxamide, exhibited no discernible inhibition of CYP450 enzymes. Conversely, distinct compounds, including 3,5-Di-tert-butylphenol and Ethyl palmitate, were found to inhibit specific CYP450 enzymes, specifically CYP2D6 and CYP1A2, respectively. Notably, Palmitic Acid demonstrated inhibition of two CYP450 enzymes, specifically CYP1A2 and CYP2C9. Furthermore, the potential for skin permeation was assessed using log Kp values, revealing that the compound 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide exhibited remarkably low skin permeation ability with a value of -6.92. For comprehensive insights into cytochrome and skin permeation attributes (Table 5).

Table 3.

Physicochemical properties of bioactive compounds in O. alismoides

S. No Compound
Name		 Molecular Weight Log P TPSA
(Å)		 Log S
(ESOL)		 Fraction
Csp3		 HBR
1. 3,5-Di-tert-butylphenol 206.32 3.87 20.23 -4.38 0.57 2
2. 2-Decynoic acid 168.23 2.47 37.30 -3.02 0.70 5
3. Tricyclo[5.2.1.0 (2,6)]decan-10-ol 152.23 2.45 20.23 -2.23 1.00 0
4. 4-Nonyne 124.22 4.38 0.00 -2.88 0.78 3
5. Palmitic Acid 256.42 4.19 37.30 -5.02 0.94 14
6. Ethyl palmitate 284.5 4.67 26.30 -5.51 0.94 16
7. 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide 244.5 0.90 55.62 -2.06 0.86 1
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Table 4.

Pharmacokinetic properties of bioactive compounds in O. alismoides

S. No Compounds Name Lipinski
Role		 BBB HIA PGP- Bioavailability
Score
1. 3,5-Di-tert-butylphenol Yes,0 Yes High No 0.55
2. 2-Decynoic acid Yes,0 Yes High No 0.85
3. Tricyclo[5.2.1.0 (2,6)]decan-10-ol Yes,0 Yes High No 0.55
4. 4-Nonyne Yes,1 Yes Low No 0.55
5. Palmitic Acid Yes,1 Yes High No 0.85
6. Ethyl palmitate Yes,1 No High No 0.55
7. 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide Yes,0 Yes High No 0.55
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Table 5.

Cytochrome properties and skin permeation of bioactive compounds in O. alismoides

S. No Compounds Name CYP1A2
inhibitor		 CYP2C19
inhibitor		 CYP2C9
inhibitor		 CYP2D6
inhibitor		 CYP3A4
inhibitor		 Log Kp
(cm/s)
1. 3,5-Di-tert-butylphenol No No No Yes No -4.07
2. 2-Decynoic acid No No No No No -4.54
3. Tricyclo[5.2.1.0 (2,6)]decan-10-ol No No No No No -5.60
4. 4-Nonyne No No No No No -4.28
5. Palmitic Acid Yes No Yes No No -2.77
6. Ethyl palmitate Yes No No No No -2.44
7. 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide No No No No No -6.92
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Molecular docking

The study examined the three-dimensional structures of different cancer-related proteins, such as Human Epidermal Growth Factor Receptor 2 (HER2), Epidermal Growth Factor Receptor (EGFR), and Estrogen Receptor Alpha (ERα), as shown in Fig. 2. These proteins were analyzed alongside seven phytocompounds from the methanol extract of O. alismoides using GC–MS analysis. The docking of these compounds with the target proteins was conducted, and the resulting data, including binding energy and hydrogen bonding, were compiled in Table 6. Notably, when tested against the HER2 protein, the bioactive compounds − 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0 (2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide, exhibited binding affinities of -4.1, -4.7, -5.6, -4.6, -4.7, -4.4, and − 6.1 kcal/mol, respectively. Noteworthy interactions were observed: 2-Decynoic acid forming hydrogen bonds with THR5 and TYR281, Palmitic Acid with THR5, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide with ASN280 and SER441 residues. Some compounds showed no hydrogen bond interactions (Fig. 4 and Table S1).

Table 6.

Molecular Docking Value of bioactive compounds in O. alismoides against Target Proteins

Target Protein
(PDB ID)		 Compound Name Binding Affinity (kcal/mol) Number of Hydrogen Bond Name of Amino acids residues
1N8Z 3,5-Di-tert-butylphenol -4.1 0 -
2-Decynoic acid -4.7 2

THR5

TYP281
Tricyclo[5.2.1.0 (2,6)]decan-10-ol -5.6 0 -
4-Nonyne -4.6 0 -
Palmitic Acid -4.7 1 THR5
Ethyl palmitate -4.4 0
2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide -6.1 2

ASN280

SER441
2J6M 3,5-Di-tert-butylphenol -3.6 2

ILE878

LYS879
2-Decynoic acid -4.7 2

MET793

GLY796
Tricyclo[5.2.1.0 (2,6)]decan-10-ol -5.4 1 THR854
4-Nonyne -4.3 0 -
Palmitic Acid -3.8 1 ASP1012
Ethyl palmitate -4.9 1 THR854
2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide -5.4 3

LYS745

THR854

ASP855
3ERT 3,5-Di-tert-butylphenol -4.1 2

MET522

GLU523
2-Decynoic acid -4.4 0
Tricyclo[5.2.1.0 (2,6)]decan-10-ol -6.3 1 GLU353
4-Nonyne -4.8 0 -
Palmitic Acid -5.2 0 -
Ethyl palmitate -4.3 0 -
2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide -6.0 0 -
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Fig. 4.

Fig. 4

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3D and 2D Structure of Estrogen Receptor Alpha with (a) 3,5-Di-tert-butylphenol; (b) 2-Decynoic acid; (c)Tricyclo[5.2.1.0 (2,6)]decan-10-ol; (d) 4-Nonyne (e) Palmitic Acid; (f) Ethyl palmitate; and (g) 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide

Similarly, against the EGFR, the binding affinities of 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0 (2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide were determined as -3.6, -4.7, -5.4, -4.3, -3.8, -4.9, and − 5.41 kcal/mol, respectively. Particularly strong interactions were observed with 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide, forming hydrogen bonds with LYS745, THR854, and ASP855. 3,5-Di-tert-butylphenol established hydrogen bonds with ILE878 and LYS879, while 2-Decynoic acid formed interactions with MET793 and GLY796. Tricyclo[5.2.1.0 (2,6)]decan-10-ol, Palmitic Acid, and Ethyl palmitate exhibited a hydrogen bond with THR854, ASP1012, and THR854, respectively. Some compounds did not show hydrogen bond interactions (Fig. 5 and Table SS2).

Fig. 5.

Fig. 5

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3D and 2D Structure of Epidermal Growth Factor Receptor with (a) 3,5-Di-tert-butylphenol; (b) 2-Decynoic acid; (c)Tricyclo[5.2.1.0 (2,6)]decan-10-ol; (d) 4-Nonyne; (e) Palmitic Acid; (f) Ethyl palmitate; and (g) 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide

Concerning ERα, the binding affinities of the bioactive compounds − 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0 (2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide - were found to be -4.1, -4.4, -6.3, -4.8, -5.2, -4.3, and − 6.0 kcal/mol, respectively. Significant interactions were observed, with 3,5-Di-tert-butylphenol establishing hydrogen bonds with MET522 and GLU523 and Tricyclo[5.2.1.0 (2,6)]decan-10-ol forming an interaction with GLU353. Some compounds did not exhibit hydrogen bond interactions (Fig. 6 and Table S3). This study highlighted the promising performance of the identified bioactive compounds, with particular emphasis on 4-Nonyne and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide. These compounds demonstrated noteworthy effects across all the cancer protein targets.

Fig. 6.

Fig. 6

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3D and 2D Structure of Human Epidermal Growth Factor Receptor 2 with (a) 3,5-Di-tert-butylphenol; (b) 2-Decynoic acid; (c)Tricyclo[5.2.1.0 (2,6)]decan-10-ol; (d) 4-Nonyne (e) Palmitic Acid; (f) Ethyl palmitate; and (g) 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide

Discussion

Natural compounds are gaining prominence in searching for lead molecules with anticancer and antioxidant properties for cancer treatment (Shapira, 2017). Although computational algorithms are extensively studied in medicinal synthetic chemistry, their application in the domain of natural phytochemicals still needs to be explored. The primary goal of molecular docking is to predict the structure of ligand-receptor complexes using computational methods (Muthusamy et al. 2011; Sathish et al. 2024). This docking process involves a virtual screening of compound libraries, with the results ranked based on scores. Theoretical models are then formulated to explain how ligands inhibit the target receptor’s activity, which is crucial for lead optimization (Feinstein and Brylinski 2015). Docking outcomes are influenced by various factors, including intramolecular forces like bond characteristics, angles, and dihedral angles, as well as intermolecular forces such as electrostatic interactions, dipolar forces, hydrogen bonds, and hydrophobic interactions (Kerns and Di 2003; Duran-Iturbide et al. 2020). In this study, the plant of O. alismoides was extracted using methanol and analyzed through phytochemical screening and in silico molecular docking. This study presents a pioneering achievement by reporting the molecular docking of O. alismoides secondary metabolites with various cancer proteins. The results highlight the solid binding capabilities of the chosen bioactive compounds to their designated receptors, suggesting molecular docking as a valuable method for identifying inhibitors. O. alismoides is known for its potential antitubercular activity, cytotoxicity and anticancer activity (TsaiYuan et al. 2012; Hoye et al. 2013).

The preliminary phytochemical analysis showed the presence of tannins, alkaloids, carbohydrates, glycosides, and steroid compounds. SahiraBanu and Cathrine 2015 reported phytochemicals of glycosides, alkaloids, flavonoids, flavones, terpenoids, tannins and phenolic compounds (SahiraBanu and Cathrine 2015). The previous report showed Alkaloids exhibit anti-inflammatory, anticancer, antimicrobial, antifungal, analgesic, anaesthetic, and neuropharmacological effects and act as pain relievers (Vijayakumar et al. 2019). Glycosides contribute antioxidant, antitumor, anticancer, antidiabetic, and hepatoprotective benefits (Kumar et al. 2017; Vijayakumar et al. 2019).

The methanol extract from O. alismoides was analyzed using GC-MS, revealing seven prominent compounds such as 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0(2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide Acid. Similarly, Seif-Eldin et al. 1998 and Thomas et al. 2013 isolated two diastereomeric 4-methylene-2-cyclohexenones, Otteliones A and B and 3a-hydroxyottelione in O. alismoides.

The compounds’ drug-likeness is contingent upon several critical physicochemical properties (Hodgson 2001). Compounds with a molecular weight of 500 g/mol or lower hold promise for easy absorption, diffusion, and transport. The compound’s lipophilic nature affects its solubility, selectivity, and permeability, all pivotal factors in determining its potential as a drug candidate (Muegge et al. 2001). Lead compounds exhibiting (XlogP3) values within the range of -0.7 to + 5.0 have demonstrated their worth. All compounds in this study adhere to this range. Overly high lipophilicity in a compound can lead to rapid metabolic turnover, reduced solubility, limited intestinal absorption, and the risk of toxicity in vital organs (Arnott and Planey 2012).

Compounds displaying polarity within the range of 20 to 130 Å and a solubility not exceeding 6 meet the acceptable benchmarks for drug-likeness. The compound’s aqueous solubility can be estimated directly from its molecular structure and weight. A fraction of carbons with sp3 hybridization no less than 0.25 serves as an efficient marker, a criterion satisfied by all compounds in this study, each surpassing the specified threshold. Flexibility, characterized by the presence of rotatable bonds (limited to 9 or fewer), plays a role in a compound’s versatility. This investigation found that Palmitic Acid and Ethyl palmitate compounds exceeded the 9-rotatable-bond limit, while the others had fewer than 9. Lipinski established the “Rule of 5” (Ro5) to define molecular characteristics of compounds for drug design assistance. The research verifies that the investigated phytocompounds fall within Lipinski’s parameters. Ro5 was applied as a filter to recognize compounds with high potential as drug candidates (Lipinski et al. 2012). The compounds found in the methanol extract of O. alismoides exhibit a high likelihood of being efficiently absorbed through the gastrointestinal tract. This implies that when taken orally, these compounds can readily cross the gastrointestinal barrier (Pires et al. 2018). In contrast, the blood-brain barrier (BBB) is a physiological partition formed by the brain’s microvascular endothelial cell layer, effectively isolating the brain from the bloodstream.

The evaluation focused on the phytocompounds’ capacity to penetrate the blood-brain barrier (BBB). Notably, 85% of the compounds could breach the BBB effectively. This ability to cross the BBB is a pivotal criterion for compounds that target the central nervous system. In contrast, ethyl palmitate exhibited an inability to traverse the BBB, which suggests a potential for minimizing adverse effects within the central nervous system. In Lin’s 2003 study, all other compounds demonstrated probabilities of BBB penetration (Lin et al. 2003). P-glycoproteins (P-gp) function as transporters located in the cell membrane’s intracellular and extracellular regions. The role of P-glycoprotein is of notable importance in drug absorption and excretion (El-Kattan and Varma 2012). The potential resistance of various compounds at distinct target sites is a significant consideration. This membrane transporter protein seems to primarily affect the limitation of cellular drug uptake from the bloodstream into the brain and from the intestinal lumen into epithelial cells, as opposed to mainly promoting the elimination of drugs from hepatic cells and renal tubules (Hunter and Hirst, 1997; Suzuki and Sugiyama 2000). The compounds 2-Decynoic acid and Palmitic Acid exhibit a higher bioavailability value of 0.85, in contrast to the remaining compounds, which possess a bioavailability value 0.55. This observation aligns with the adherence of these compounds to the Lipinski rule of five, implying a 55% probability of bioavailability. The vital aspect of drug design lies in the oral bioavailability of a drug, which denotes the portion of the administered dose that reaches the bloodstream. The process is mainly influenced by gastrointestinal absorption. A drug’s aqueous solubility should be favourable for optimal oral bioavailability and absorption (Levin 2012; Veber et al. 2002).

The enzyme Cytochrome P450 monooxygenase is crucial to drug metabolism and elimination in biological systems. Around 90% of the molecules under investigation in this study serve as substrates for five distinct isoforms of the enzyme: CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 (Stegemann et al. 2007). These compounds exhibit no inhibitory effects on the activities of these enzymes, implying a strong likelihood of undergoing transformation and subsequent bioavailability following oral administration. Notably, these compounds do not hinder the functioning of CYP450 enzymes and do not provoke any adverse reactions. Nevertheless, it’s essential to recognize that if these compounds were to inhibit the CYP isoenzymes, it could disrupt the metabolism process, potentially leading to decreased bioavailability and the risk of accumulating in the body, which could have toxic effects (Srimai et al. 2013). Within the range of compounds studied, a subset does display inhibitory actions on CYP450 enzymes, which could result in unforeseen adverse reactions. This inhibition of specific enzyme variants raises significant concerns regarding potential interactions between different drugs, particularly in relation to the movement and processing of drugs within the body. Such inhibition, combined with the possibility of accumulation, has the potential to impact critical aspects of drug behaviour, including absorption, distribution, metabolism, and excretion (ADME), which could ultimately lead to unfavourable consequences (Wang et al. 2015). The skin serves as a discerning barrier, allowing the entry of diverse compounds for penetration. Skin permeability holds significant importance in appraising compounds suitable for transdermal administration. A molecule’s skin permeability, indicated by its negative logarithmic Kp value, is inversely proportional to its permeation potential—lower values correspond to reduced permeability. In this current research, all compounds exhibit impermeability, as reflected by their negative logarithmic Kp values (Raies and Bajic 2016).

Our investigation encompassed molecular docking studies involving phytocompounds from O. alismoides and their interactions with three distinct cancer proteins. The primary focus was on how these phytochemicals interacted with the active sites of the target proteins, potentially enhancing their functional roles. Notably, the phytocompounds identified in our study adhered to the Lipinski rule of five, indicating their probable safety for human consumption. The study extensively covered various aspects, including binding affinity, specific bonding patterns like hydrogen bonds, the interactions between ligand amino acid residues and the protein, and the bond lengths between ligand atoms and target proteins.

Valeriote et al. (2002) assessed the target protein binding strengths in kcal/mol for all phytocompounds (ligands). The study accurately pinpointed the locations where the ligands attached to specific amino acids on the protein structure. Encouragingly, all compounds exhibited favourable binding affinities. For instance, in the case of the HER2 protein, compounds including 3,5-Di-tert-butylphenol, 2-Decynoic acid, Tricyclo[5.2.1.0(2,6)]decan-10-ol, 4-Nonyne, Palmitic Acid, Ethyl palmitate, and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide showcased binding affinities of -4.1, -4.7, -5.6, -4.6, -4.7, -4.4, and − 6.1 kcal/mol, respectively. Similarly, concerning the EGFR protein, the binding affinities were − 3.6, -4.7, -5.4, -4.3, -3.8, -4.9, and − 5.4 kcal/mol for the mentioned compounds. As for the ERα protein, binding affinities were measured at -4.1, -4.4, -6.3, -4.8, -5.2, -4.3, and − 6.0 kcal/mol, respectively. These binding affinities are comparable to those reported for standard drugs against the same target proteins. For instance, Mendie and Hemalatha (2022) documented binding energies of -6.03 kcal/mol and − 6.59 kcal/mol for Dovitinib and Gefitinib against HER2, respectively. Similarly, Yusuf et al. (2023) studied molecular docking of the standard drug Erlotinib against EGFR protein, which has a binding energy of -8.539 kcal/mol. Another study showed a binding energy of -8.2 kcal/mol for Gemcitabine against the ERα protein (Munshi et al. 2022). Therefore, it can be inferred from the molecular docking studies that Tricyclo[5.2.1.0(2,6)]decan-10-ol and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide have good affinity for the target proteins.

Conclusion

The present study investigated the methanol extract of O. alismoides. GC-MS analysis revealed seven bioactive compounds with favorable physicochemical properties according to SwissADME, falling within recommended ranges for molecular weight, Log P, and TPSA. Additionally, most ADMET properties, including bioavailability, logS, human intestinal absorption, and BBB permeation, were within acceptable ranges, suggesting their potential as drug candidates. Furthermore, a majority of the phytoconstituents exhibited promising bioactivity scores, cytochrome properties, and skin permeation, indicative of good drug-like characteristics. Molecular docking studies revealed promising binding affinities of these compounds against selected target proteins, particularly Tricyclo[5.2.1.0(2,6)]decan-10-ol and 2,2,6-Trichloro-7-oxabicyclo[4.1.0]heptane-1-carboxamide, which showed the highest binding affinities with ERα, HER2, and EGFR. Notably, no prior in silico studies have investigated this plant’s effects on cancer proteins. Further in vitro and in vivo investigations are warranted to validate these findings comprehensively.

Electronic supplementary material

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Supplementary Material 1 (55.5KB, doc)

Acknowledgements

The authors gratefully acknowledge the SR Academy and Management of J.J. College of Arts and Science (A), Pudukkottai, for providing lab facilities, to carry out this research work.

Abbreviations

GC-MS

Gas Chromatography and Mass Spectrum

WHO

World Health Organization

ADMET

Absorption, Distribution, Metabolites, Excretion and Toxicity

PDB

Protein Data Bank

PDBQT

Protein Data Bank, Partial Charge (Q), & Atom Type (T)

TPSA

Topological Polar Surface Area

BBB

Blood-Brain Barrier

Ro5

Rule of 5

CYP

Cytochrome P450

HER2

Human Epidermal Growth Factor Receptor 2

EGFR

Epidermal Growth Factor Receptor

ERα

Estrogen Receptor Alpha

THR

Threonine

TYR

Tyrosine

ASN

Asparagine

SER

Serine

LYS

Lysine

ASP

Aspartic Acid

ILE

Isoleucine

MET

Methionine

GLY

Glycine

GLU

Glutamic acid

Author contributions

SM., SS and CR., wrote the main manuscript text and JP.,JP., and SM., prepared all figures and tables. All authors reviewed the manuscript.

Declarations

Supporting information

This manuscript contains supplementary file.

Conflict of interest

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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