Abstract Prostate cancer (PCA) is the most prevalent one among men all-inclusive, affecting men in over 112 countries. It is expected to upsurge from 1,400,000 instances in 2020 to 2,900,000 incidents by 2040. The purpose of the present investigation was to evaluate the anticancer properties of bioactive components extracted from Alpinia purpurata (A. purpurata) leaf extract with the C-X-C chemokine receptor type 4 (CXCR4) and phosphatase and tensin homolog (PTEN) receptor protein targets in comparison to the conventional drug Finasteride. Bioactive chemicals from this plant have not yet been identified as a treatment for PCA.  The ethyl acetate extract of A. purpurata was subjected to fractionation using column chromatography and characterization using spectroscopic analysis followed by molecular docking were carried out by Computational methods.  Pentatriacontanoic acid, Nonacosanol and triacontanol were the compounds isolated and characterized from the ethyl acetate extract of A. purpurata. All the three compounds used in this study qualify to be drug candidates according to the Absorption, Distribution, Metabolism, and Excretion (ADME) properties predictions and of these pentatriacontanoic acid, 1-nonacosanol and triacontanol show good anticancer potential. The three isolated compounds, pentatriacontanoic acid might render strong anti-tumour effects. Ultimately, it can be stated that pentatriacontanoic acid has the potential to be an effective treatment for PCA.

Keywords: Prostate cancer, Alpinia purpurata, Finasteride, Pentatriacontanoic acid, CXCR4, PTEN

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Citation:  Palanirajan, A., Kannappan, P., Manikandan, V.R., Chandrasekaran, M.K., Ahalliya, R.M., Jothinathan, M.K.D., and Kanniappan, G.V. 2026. Isolation and structural characterization of bioactive compounds from Alpinia purpurata targeting prostate cancer receptors CXCR4 and PTEN: A molecular docking approach. Natural and Life Sciences Communications. 25(3): e2026056.

Graphical Abstract:

INTRODUCTION

Prostate cancer (PCA) is the most predominant one among men all-inclusive, plaguing 112 countries. It is predictable to increase from 1,400,000 instances in 2020 to 2,900,000 incidents by 2040. This ailment is ranked second in terms of mortality, after lung cancer (James et al., 2024). The IARC and GLOBOCAN investigate 10,065,305 additional cases worldwide. 34,540 new cases of PCA with approximately 16,873 deaths have been found in India. About 115,426 and 106,139 cases have been reported from China and Japan, respectively. Estimates reveal that 13,426 deaths were reported in Japan and 51,094 deaths in China (Deshmukh et al., 2024). PCA is a diverse, slowly progressing, slowly progressive malignancy. Age, ethnicity, and past familial relationships of PCA are documented as jeopardy reasons for this illness. Men identified with stages I and II have an almost 100% survival rate, while men diagnosed with stages IV have a 50% survival rate (Hall et al., 2024). It is becoming more prevalent in South Asia with poor awareness and screening rates. Studies show a significant lack of understanding and awareness of PCA in the region (Kumar et al., 2025). Common diagnosis of this disease encompasses tissue biopsy followed by the estimation of prostate-specific antigen. The preliminary biopsy examination is used for the establishment of therapy strategies for localized PCA. With this, the pathologists assign a Gleason grade grouping by assessing the haematoxylin and eosin-stained tissues (Zhu et al., 2024).

C-X-C chemokine receptor type 4 (CXCR4) is a G-protein coupled receptor superfamily and has been shown to have a crucial part in many biochemical processes, such as immune cell trafficking and homeostasis. CXCR4 Mutations are observed in the majority (94.2%) of metastatic prostate tumours (Hassanshahi et al., 2021). Overexpression of CXCR4 drives PCA metastasis by enhancing PCA cells' motility and invasion potential toward C-X-C motif chemokine ligand 12 (CXCL12). The interactions of chemokine CXCL12 and CXCR4 receptor seems to have an integral part in the dissemination of prostate tumor cells from the primary site (prostate) to secondary site (bone) (Adekoya and Richardson, 2020). Phosphatase and tensin homolog (PTEN) is the 2nd most often mutant gene in human malignancies, following p53. PTEN is a phosphatase that is widely recognized for its role in tumor suppression via inhibiting the PI3K pathway. PTEN deletions and/or mutations were identified in thirty percent of benign prostate tumors and sixty-three percent of disseminated prostate biopsy specimens, making PTEN mutations the most frequent genetic abnormalities observed in human prostate malignancies (Wang et al., 2020).

Natural compounds from many species are commonly used to treat and manage diseases particularly cancer and infections (Atanasov et al., 2021; Jalil et al., 2024). The WHO claims that about eighty percent of the global population trusts on plant-based medical products for standard healthcare (Suresh Kumar et al., 2024). Researchers are increasingly interested in using plant secondary metabolites as natural medicines for treating chronic diseases. According to research findings, natural substances outperform synthetic drugs with respect to of pharmacokinetic and pharmacodynamic features.  As a result, recent research has centred on isolating and synthesizing plant bioactive substances in large scale (Sivapragasam et al., 2024).

Free radicals are unstable chemicals that can cause DNA damage. Radical damage to DNA and proteins is a crucial factor in cancer formation (Balqis et al., 2022). Medicinal plant-based cancer medicines are effective, cost-efficient, and have low side effects.

The discovery of therapeutic capabilities in food plants has led to a demand for novel cancer therapies (Boontha et al., 2024). Plant-derived phytochemicals such as polyphenols, carotenoids, vitamins and others play an important role as natural antioxidants (Mukherjeeet al., 2024). Zingiberaceae (Ginger) plants have a variety of therapeutic characteristics (Kumar et al., 2006). The genus Alpinia has been intensively researched for its anticancer potential. Various compounds from these species have been claimed to have properties for the prevention and treatment of cancer (Surh, 1999). To date, no bioactive components from this plant have been identified to treat PCA. Alpinia purpurata (A. purpurata) has been utilized in traditional Chinese medicine (TCM) PCA treatment by triggering the apoptosis in scientific validation (Anusooriya et al., 2022). The studies focused on tracing the active ingredients of A. purpurata utilizing isolation techniques and discovered three, C28-C30 fatty acids.

While long-chain fatty acids and alcohols have been previously identified from several members of the Zingiberaceae family, such as Alpinia galanga and Zingiber officinale, their biological relevance to PCA remains unexplored. The present study is the first to report the isolation of pentatriacontanoic acid, 1-nonacosanol, and triacontanol from A. purpurata and to evaluate their potential interactions with key PCA targets using molecular docking. The novelty of this work lies in establishing a mechanistic link between naturally occurring long-chain lipid derivatives from A. purpurata and their binding affinity toward oncogenic receptors associated with PCA progression. The rationale for selecting CXCR4 and phosphatase and tensin homolog (PTEN) as dual docking targets stems from their complementary roles in tumor biology: CXCR4 mediates tumor invasion and metastasis through the CXCL12 signaling axis, whereas PTEN acts as a tumor suppressor regulating the Phosphoinositide 3-kinase (PI3K) / Protein Kinase B (AKT) / Mechanistic Target of Rapamycin (mTOR) (PI3K/AKT/mTOR) pathway. Co-targeting these pathways may therefore provide a synergistic therapeutic approach against PCA. In this context, the present study combines phytochemical isolation, structural elucidation, and in silico docking to identify natural compounds from A. purpurata with potential dual inhibitory activity against CXCR4 and PTEN.

MATERIALS AND METHODS

Plant collection and authentication

A. purpurata (Vieill.) K. Schum. leaves were obtained from the native surroundings of Kanyakumari district, Tamil Nadu, India, in July 2014. The plant specimen was authenticated at the Botanical Survey of India, TNAU, Coimbatore, and a voucher specimen was deposited in the herbarium of Karpagam University, Coimbatore, for future reference (BSI/SC/5/23/10-11/Tech). Approximately 10 kg of fresh leaves were collected, thoroughly cleaned, and shade-dried at room temperature for seven days until a constant weight was achieved. The dried material was then pulverized to obtain 1.2 kg of fine powder, yielding an approximate fresh-to-dry weight ratio of 8.3:1. The powdered material was used for subsequent extraction and analysis.

Preparation of ethyl acetate extract

Based on prior research, 200 g of powdered plant sample was suspended with 1L of ethyl acetate as menstrum at ambient temperature. The resulting extract was obtained and concentrated utilizing a rotary evaporator at 40°C. The concentrated extract dry weighing 6.8g (3.4%) was stored for fractionation.

Fractionation

Compounds are isolated from crude plant extracts into pure components through molecular polarity and adsorption on the adsorbent (Mukherjee et al., 2024). Column chromatography is a popular approach for fractionating and isolating biomolecules. The column chromatography (4 × 100 cm) was performed using 60-120 mesh silica gel to elute out individual compounds.

The extracted plant sample (3.4 g) was further subjected to column chromatography (CC) using a glass column (60 cm × 2.5 cm) packed with silica gel (60–120 mesh; Merck). Elution was carried out with a gradient of solvents in increasing polarity, starting with petroleum ether followed by chloroform, ethyl acetate, methanol, and water. Solvent ratios were varied from 100:0 to 0:100 (v/v) in 10% increments. Each fraction (20 mL) was collected and monitored by thin-layer chromatography (TLC) on silica gel 60 F254 plates using appropriate solvent systems. A total of 110 fractions (each 20 ml) were obtained from the column as illustrated in Table 1.

Table 1 Separation of active constituents from column chromatography.

Further, the fractions were subjected to TLC analysis (Kaliaperumal et al., 2023). Fractions from 12 to 21^st, from 27-30^th, and 47^th revealed vivid spots on TLC plates with silica gel as stationary phase. The solvent systems used were ethyl acetate: chloroform (5:5), ethyl acetate: chloroform (5:5), and 100% methanol. An exclusive spot was visualized under iodine fumes. From this, it might suggest the existence of a single chemical compound. The Retention factor (Rf) values for each of the 3 isolated compounds were obtained. Three isolated compounds weighing 69 mg, 41 mg, and 83 mg respectively were employed for subsequent studies.

Characterization of isolated compounds using nuclear magnetic resonance (NMR)

The isolated compound's structure was elucidated using proton (¹H) and carbon (¹³C) NMR spectroscopy. Optical rotation of the solution was calculated using a polarimeter (Perkin-Elmer 341). NMR spectra of CDCl₃ solutions were acquired on a spectrometer (Bruker Advance DRX 500) at 500 MHz for ¹H and 125 MHz for ¹³C; the deuterated solvent signals were used as a reference. The ¹H and ¹³C NMR spectra provided representative chemical shift assignments (C1–C6) to highlight characteristic proton and carbon environments corresponding to long-chain fatty acids and alcohols. The full spectra are provided in the supplementary material to ensure transparency and reproducibility.

Computational studies

The isolated and characterized compounds from the sample extract were docked using Glide 5. 0 installed with 3.4 GHz Pentium 4 processor with Red Hat Linux Enterprise version 5.0 as the operating system.

Target proteins retrieval and preparation

The three-dimensional structures of the CXCR4 and PTEN proteins (PDB entries 3ODU and 1D5R) were retrieved from Protein Data Bank and proteins were prepared by protein preparation wizards (standard methods) that are available in grid-based ligand docking with energetic (Protein Preparation Wizard (Berman et al., 2002; Friesner et al., 2004). The active site (binding pocket) and functional residues of CXCR4 and PTEN were identified and characterized by site-map module from Schrodinger package. Pre-processed bond orders were designated, hydrogen molecules were introduced, and water molecules were eliminated. RMSD 0.330˚A was used to minimize energy (Impref minimization). The three-dimensional structures of the ligand molecules were generated using Maestro 8.5 (Schrodinger's Suite). The ligands were then designed using the OPLS-2005 force field (Hopkins et al., 1996; Jorgensen et al., 1996), O and the atomic charges were calculated accordingly. The docking grid was defined around the active site residues of each target protein based on the co-crystallized ligand coordinates from their respective PDB structures (CXCR4: 3ODU; PTEN: 1D5R). A cubic grid box of 20 × 20 × 20 Å was generated, centered on the ligand-binding cavity. Validation of the docking protocol was performed by redocking the native co-crystallized ligand into the corresponding receptor site, yielding an RMSD value of < 2.0 Å, confirming the reliability of the docking parameters. Glide XP mode was then used for ligand docking, and both Glide score (kcal/mol) and Glide energy (kcal/mol) were recorded. Binding interactions, including hydrogen bonding and hydrophobic contacts, were analyzed using Maestro’s Pose Viewer and visualized in LigPlot+. Glide scores represent the predicted binding affinity, where lower values correspond to stronger predicted binding interactions. (Dhamodiran et al., 2024).

Preparation of ligands

The ligand molecules utilized in the Glide docking analysis were generated within Maestro using the Schrodinger Inc. build module Lig Prep 2.4. These structures were geometrically optimized using the Optimized Potentials for Liquid Simulations-2005 (OPLS 2005) force field, followed by a truncated Newton conjugate gradient methodology. atomic charges were calculated using the OPLS_2005 force field. The isolated bioactive compound was docked in to the binding site CXCR4 and PTEN using GLIDE.

ADME profiling

The “Human oral absorption” (HOA) parameter in Table 5 is expressed as a categorical scale in QikProp, where 1 = low, 2 = medium, and 3 = high predicted absorption. All isolated compounds scored “1,” indicating low but acceptable absorption potential typical of long-chain lipophilic molecules, which may be enhanced through formulation optimization. Other ADME descriptors (QPlogPo/w, donor/acceptor hydrogen bonds, and Lipinski’s violations) confirmed the overall drug-likeness of the compounds. It is used to forecast physicochemically and pharmacokinetically important characteristics. QikProp provides parameters for comparison of the molecular attributes to 95% of previously identified medications. It also assesses the appropriateness of ligands using Pfizer's rule of five, which is critical for assuring pharmacodynamic and kinetic profiles of a drug. (Lipinski et al., 2001).

RESULTS

Thin layer chromatography (TLC) analysis of the isolated compounds from A. purpurata revealed distinct Rf values for pentatriacontanoic acid (0.54), 1-nonacosanol (0.60), and triacontanol (0.50) (Figure 1).

Figure 1. Thin layer chromatography (TLC) analysis of the isolated compounds from A. purpurata.

The UV spectra exhibited absorption maxima at 252 nm, 271 nm, and 241 nm, characteristic of long-chain saturated fatty acids and alcohols lacking strong chromophoric groups, which agrees with previously reported spectra for similar compounds isolated from Alpinia galanga and Zingiber officinale. (Oliver et al., 2010; Mori et al., 2020) (Figure 2).

Figure 2. Ultraviolet (UV) analysis of the isolated compounds from A. purpurata.

FTIR spectra of pure compounds are usually unique, acting as a “molecular fingerprint” (Amin et al., 2025). The Shimadzu FTIR Spectrum instrument consists of globar and mercury vapour lamp as sources, an interferometer chamber comprising of KBr and Mylar beam splitters followed by a sample chamber and detector. Entire region of 450-4,000 cm^-1 is covered by this instrument. The spectrometer works under purged conditions. Solid samples are dispersed in KBr or polyethylene pellets depending on the region of interest. This instrument has a typical resolution of 1.0 cm^-1. Signal averaging, signal enhancement, base line correction and other spectral manipulations are possible.

FTIR spectra confirmed the presence of characteristic functional groups: pentatriacontanoic acid displayed absorption bands at 3,415 cm⁻¹ (OH), 1,720 cm⁻¹ (C=O), and 1,070 cm⁻¹ (C–O), while 1-nonacosanol showed peaks at 3,426 cm⁻¹ (OH), 2,927 cm⁻¹ (C–H), and 1,061 cm⁻¹ (C–O). Triacontanol exhibited bands at 2,927 cm⁻¹ (C–H), 1,718 cm⁻¹ (C=O), and 1,076 cm⁻¹ (C–O) (Figure 3; Table 2).

Table 2. Functional group analysis of three isolated compounds using FTIR.

Figure 3. Fourier transform infrared (FTIR) analysis of the isolated compounds from A. purpurata.

Table 3. ¹H NMR and ¹³C NMR spectrum of three isolated compounds using JEOL GSX 400 NB FT-NMR spectrometer.

Figure 4.  ¹H NMR spectrum of the compounds from A. purpurata.

The ¹H and ¹³C NMR spectra (Figures 4–5; Table 3) further supported the identity of the compounds. Pentatriacontanoic acid exhibited characteristic δ values at 0.83 (terminal CH₃), 1.29 (long-chain CH₂), 2.27 (α-CH₂ to carbonyl), and 4.05–4.12 (O-CH₂). The carbonyl group resonance appeared at δ 172.00, consistent with long-chain fatty acid esters. 1-Nonacosanol exhibited a δ 64.00 resonance for O–CH₂ carbon, alongside CH₃ and CH₂ peaks. Triacontanol displayed signals at δ 0.83 (CH₃), 1.29 (CH₂ chain), and 172.00 (C=O).

Mass spectral analysis (Figure 6) revealed molecular ion peaks at m/z 504 [(M–H₂O)⁺, MW 522] for pentatriacontanoic acid, m/z 424 (MW 424) for 1-nonacosanol, and m/z 438 (MW 438) for triacontanol, confirming their molecular formulas as C₃₅H₇₀O₂, C₂₉H₆₀O, and C₃₀H₆₂O, respectively (Figure 7).

Molecular docking revealed strong binding interactions of the compounds with PCA targets CXCR4 and PTEN (Figures 8–10). Pentatriacontanoic acid showed the strongest binding with CXCR4 (Glide score –6.65; Glide energy –49.19 kcal/mol), followed by triacontanol (–6.77; –46.66 kcal/mol) and 1-nonacosanol (–6.19; –42.16 kcal/mol). Pentatriacontanoic acid also bound PTEN with a Glide score of –2.78 and Glide energy of –55.79 kcal/mol, surpassing the reference drug Finasteride (–2.96; –37.74 kcal/mol). ADME profiling indicated that all three compounds fulfilled drug-likeness criteria (Table 5).

Figure 5.  ¹³C NMR spectrum of the compounds from A. purpurata.

Figure 6. Mass spectroscopy analysis of isolated compounds from A. purpurata.

Figure 7. Structure of three isolated compounds from A. purpurata.

Table 4. Binding efficacy of isolated compounds and standard commercial drug with CXCR4 and PTEN target proteins.

All the three isolated compounds have better interaction with CXCR4 and obtained prominent glide score with glide energy relative to the FDA approved Standard Finasteride. CXCR4-pentatriacontanoic acid complex, has good interaction, G score of -6.65 with the Glide energy - 49.19 and the O atom interact with Arginine residue (Figure 8a).

Figure 8. Docking complex of CXCR4 with Pentatriacontanoic acid (a),  1-Nonacosanol (b), Triacontanol (c), Finasteride (STD) (d) generated by using Glide-XP module of Schrödinger suite are shown in these figures as 3D Structure.

CXCR4 - 1-nonacosanol complex and CXCR4- Triacontanol complex also had a better interaction obtained better G score - 6.19 and - 6.77 with G energy - 42.16 and - 46.66 respectively (Figure 8b, 8c). CXCR4 – 1-nonacosanol complex shown in Figure 9 (b), the Complex has an OH atom interacted with lysine residue. In Figure 9 (c), shown, the CXCR4 – Triacontanol complex has an OH atom interacted with histidine residue.

Figure 9. Docking complex of CXCR4 with Pentatriacontanoic acid (a), 1-Nonacosanol (b), Triacontanol (c), Finasteride (STD) (d), The 2D Graphics, pink color arrows and dotted lines indicate 'Hydrogen bonds' between the corresponding atoms at the back bone or side chains of the receptor respectively with the compound.

Figure 10. Docking complex of PTEN with Pentatriacontanoic acid (a), Finasteride (STD) (c) generated by using Glide-XP module of Schrödinger suite are shown in these figures as 3D Structure; Docking complex of PTEN with Pentatriacontanoic acid (b), Finasteride (STD) (d), The 2D Graphics, pink color arrows and dotted lines indicate 'Hydrogen bonds' between the corresponding atoms at the back bone or side chains of the receptor respectively with the compound.

Table 5. ADME profiling of isolated compounds and standard commercial drug.

DISCUSSION

The isolation and structural characterization of pentatriacontanoic acid, 1-nonacosanol, and triacontanol from A. purpurata add to the growing list of long-chain lipid derivatives with potential pharmacological activity. TLC, UV-Vis, FTIR, NMR, and Mass spectrometry confirmed their molecular identities, while the presence of hydroxyl and carboxyl groups provided the chemical basis for strong polar interactions in agreement with previous reports (Oliver et al., 2010; Singla and Ali, 2018; Mori et al., 2020). The ability of the carboxyl group in pentatriacontanoic acid to form hydrogen bonds with positively charged amino acid residues such as arginine likely underpins its superior affinity compared to the long-chain alcohols.

The strong cytotoxic activity of pentatriacontanoic acid against PC-3 cells, reported previously with an LD₅₀ of 111.17 μg/mL (Anusooriya et al., 2017), suggests its potential as a bioactive anticancer compound. Similarly, triacontanol has been recognized for its pharmacological properties, including growth regulation and anticancer potential (Liu et al., 2021).

In silico studies showed that these compounds interact favourably with two critical PCA targets, CXCR4 and PTEN, with pentatriacontanoic acid exhibiting the strongest binding energies. The ability of the carboxyl group in pentatriacontanoic acid to form hydrogen bonds with positively charged amino acid residues such as arginine likely underpins its superior affinity compared to the long-chain alcohols.

CXCR4 is a chemokine receptor that plays a vital role in tumor development, invasion, and bone metastasis of PCA. Its ligand, CXCL12, promotes cancer cell migration and metastatic colonization of bone, and overexpression of CXCR4 is consistently associated with poor clinical outcomes (Singh et al., 2004; Conley-LaComb et al., 2016). Pharmacological inhibition of CXCR4 has been shown to impair metastatic spread and sensitize tumor cells to therapy (Buck et al., 2022).  PTEN, on the other hand, is a tumor suppressor frequently lost or mutated in PCA, leading
to constitutive activation of the PI3K/AKT/mTOR pathway, tumor cell survival, and aggressive disease (Jamaspishvili et al., 2018). In vivo studies also reported immunomodulatory and tumor-suppressive activities of triacontanol (Zhou et al., 2018).

Interestingly, pentatriacontanoic acid showed stronger interaction with PTEN compared to the FDA-approved drug Finasteride, suggesting its therapeutic promise in PCA. The interactions with key amino acid residues (lysine, arginine, histidine) support its stability and specificity. These results align with epidemiological evidence indicating that phytosterols and long-chain fatty alcohols exert protective roles against cancers, including breast, colon, and prostate malignancies (Saha et al., 2021; Sara et al., 2021).

Overall, the findings indicate that long-chain fatty acids and alcohols from A. purpurata can interact strongly with PCA targets, with pentatriacontanoic acid emerging as the most promising scaffold. Future studies should include in vitro assays on PCA cell lines, functional validation of CXCR4/AKT pathway inhibition, and in vivo tumor models to determine therapeutic potential. Structural optimization and delivery systems may further enhance solubility and potency. This work highlights the relevance of natural lipid derivatives as candidate molecules for developing novel therapeutic strategies against PCA.

CONCLUSION

The results obtained from all these analyses; it can be inferred that the A. purpurata possess potent anticancer efficacy to combat prostate carcinogenesis. Among the three isolated compounds, pentatriacontanoic acid might may exhibit anti-tumour potential. As a result, this compound has the potential to be a promising pharmacological candidate for PCA treatment in future years.

ACKNOWLEDGEMENTS

We, the authors are thankful to our Chancellor, Chief Executive officer, Vice-Chancellor, and Registrar of Karpagam Academy of Higher Education for providing facilities and encouragement. Our thanks are also due to Sophisticated Analytical Instrument Facility (SAIF), Cochin University of Science and Technology, Cochin and Indian Institute of Technology, Chennai, India for successful NMR and MS analysis respectively.

AUTHOR CONTRIBUTIONS

Anusooriya Palanirajan: Conceptualization (Lead), Methodology (Lead), Formal Analysis (Lead), Validation (Lead), Writing – Original Draft (Lead), Writing – Review & Editing (Lead), Investigation (Equal); Poornima Kannappan: Conceptualization (Lead), Data Curation (Equal), Formal Analysis (Equal), Writing – Review & Editing (Equal); Manikandan Vani Raju: Data Curation (Equal), Formal Analysis (Equal), Methodology (Equal), Resource (Lead); Meenakshi Kaniyur Chandrasekaran: Data Curation (Equal), Formal Analysis (Equal), Methodology (Equal); Rathi Muthaiyan Ahalliya: Methodology (Supporting), Formal Analysis (Supporting), Resource (Lead), Writing – Review & Editing (Equal); Mukesh Kumar Dharmalingam Jothinathan: Methodology (Lead), Resource (Equal), Writing – Review & Editing (Lead); Gopalakrishnan Velliyur Kanniappan: Conceptualization (Lead), Methodology (Lead), Validation (Lead), Writing – Review & Editing (Lead), Supervision(Equal).

CONFLICT OF INTEREST

The authors declared no conflict of interest in the manuscript.

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