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. 2021 Aug 10;9(1):50. doi: 10.1007/s40203-021-00099-6

Identification of α-amylase inhibitors from flavonoid fraction of Feronia elephantum and its integration with in-silico studies

Saikiran Kulkarni 1,#, Prarambh Dwivedi 1,#, Aravinda Nagaraj Danappanvar 1, Belgaonkar Ashwini Subhash 1, B M Patil 1,✉
PMCID: PMC8353021  PMID: 34458069

Abstract

Postprandial hyperglycemia is associated with an increase in blood glucose levels after a meal, which is further associated with various risk factors like cardiovascular diseases. α-amylase is a digestive enzyme and secreted by the salivary glands and pancreas, which helps to catalyze the hydrolysis of the internal α-1,4-glycosidic linkages in starch breaking them into smaller units. Hence, the present study is aimed to identify flavonoids from the fruit pulp of Feronia elephantum as α-amylase inhibitors via in-silico and in-vitro protocols. In-silico tools like ADVERPred, PubChem, MolSoft, Discovery studio 2019, and Autodock 4.0 were used to predict the information related to phytoconstituents, drug-likeness character, and probable side effects. In-vitro α-amylase inhibitory activity was performed with five different concentrations of flavonoid fraction of hydroalcoholic extract of the fruit pulp of Feronia elephantum using 1% starch solution and DNS reagent. Four flavonoids were identified from 25 bio-actives present in the fruit pulp of Feronia elephantum. Three bio-actives were predicted to possess a positive drug-likeness score, from which 5,4-dihydroxy3-3(3-methyl-but2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-Glucopyranoside was predicted to possess the highest drug-likeness score of 0.70. Vitexin and 5,4-dihydroxy3-3(3-methyl-but2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-Glucopyranoside were predicted to possess nephrotoxicity as an adverse effect. The percent inhibition of α-amylase by a flavonoid-rich fraction at 100 μg/ml was found to be 45.95% as compared to standard acarbose with 74.79% inhibition at 100 μg/ml. Further, docking studies predicted that vitexin possessed the highest binding affinity (binding energy − 7.98 kcal/mol) as compared to standard acarbose with binding energy − 5.24 kcal/mol. There were no significant side effects predicted, in-vitro α-amylase inhibitory activity of the flavonoid-rich fraction may be due to the presence of vitexin, predicted via in-silico molecular docking; further, which needs to be further validated via in-vivo protocols.

Keywords: α-Amylase, Feronia elephantum, Flavonoids, In-silico, Vitexin

Introduction

Diabetes mellitus (DM) is a metabolic disorder leading to hyperglycemia, glycosuria, and sometimes ketonemia (Craig et al. 2007). A study performed on the global prevalence of diabetes estimated that by the year 2030 around 171 million would be diagnosed with diabetes mellitus (Wild et al. 2004). Type 1 DM, occurs due to the destruction of β cells of the pancreas, and the capability of maintaining blood glucose via insulin release is demolished (Ozougwu et al. 2013). Similarly, type 2 DM involves improper functioning of β cells of the pancreas caused due to abnormality in gluco-receptor of β cells or due to reduced sensitivity of peripheral tissues to insulin (NIKI and NIKI 1980; Khanal and Patil 2021). DM is a chronic disorder and is often subjected to chronic therapy of oral anti-diabetic drugs which would supplement insulin, and includes sulfonylureas, metformin, thiazolidinediones, etc. although established therapy of their agents available possesses various unwanted side effects (Dwivedi et al. 2021a, b). Further, postprandial hyperglycemia (PPHG) is defined as a condition wherein there is an elevation of blood glucose level after consumption of a meal and is also associated with risk factors for cardiovascular disorders (Kazeem et al. 2013).

α-Amylase is a digestive enzyme, and prominent secretory product of the salivary gland and pancreas hydrolyzes 1,4-glycosidic linkages of dietary starch and various oligosaccharides into maltose, maltotriose, and simple sugars in the intestinal mucosa (Ternikar et al. 2020; Mwakalukwa et al. 2020). The intestinal brush border consists of α-glycosidase which breaks down oligosaccharides and further gets absorbed from the intestinal mucosa to the portal blood, through glucose transporter (GLUT2) and sodium-glucose co-transporter 1 (SGLT1), leading to postprandial hyperglycemia (PPHG) (Martinez-Gonzalez et al. 2017; Proença et al. 2019). Inhibition of this enzyme delays carbohydrate digestion, thus drastically reduces glucose absorption through the intestinal mucosa, consequently minimizing the postprandial glucose rise (Alam et al. 2019).

Feronia elephantum Correa (synonym: Feronia limonia, Schinus Limonia or Limonia acidissima, Murraya odorata; common names: Bela, Billin, Kath, kavitha), belonging to the family Rutaceae (Muthulakshmi et al. 2012; Dwivedi et al. 2021a, b) has been used to treat diabetes and other clinical conditions such as diarrhea, pruritus, impotence, dysentery, heart diseases and are also used as a liver tonic (Mishra and Garg 2011). The fruit pulp of Feronia elephantum is rich in flavonoids, glycosides, saponins, tannins, and β-carotene which is a precursor of vitamin A and has been used for the management of diabetes mellitus (Reddy et al. 2019). Thus, the present study is aimed to identify α-amylase inhibitors from the flavonoid-rich fraction from the fruit pulp of Feronia elephantum via system biology tools and validating results via in-vitro α-amylase inhibitory activity.

Material and methods

Collection of plant

Wild grown ripe fruits of the plant Feronia elephantum were collected from local areas of Belagavi, India. The collected plants were authenticated by a botanist in the Indian Council of Medical Research-National Institute of Traditional Medicine (ICMR-NITM), Belagavi, and the herbarium was deposited for the same (Accession No. RMRC-1617) for future reference.

Preparation of hydro-alcoholic extract

The collected plant F. elephantum was washed under running water, shade dried, and turned into a coarse powder. Briefly, the coarse powder was macerated with 70% ethanol with occasional shaking for 7 d followed by filtration; marc was then subjected for soxhlet extraction using 95% ethanol. Later, both the filtrates were combined, concentrated under a rotary evaporator (IKA RV 10), and reduced pressure which yields 11.25% extract of F. elephantum (Cos et al. 2006). Later, fractionation was performed as explained by Khanal and Patil (2020a, b).

Mining of flavonoid bio-actives

The bio-actives present in the flavonoid-rich fraction of Feronia elephantum was reformed from the published research and review articles. The molecular formula, molecular weight, PubChem CID, and InChI key were retrieved from the PubChem database (Kim et al. 2021).

In-vitro α-amylase inhibitory assay

Fraction rich flavonoid was subjected as a test sample and was diluted to prepare a concentration of 100 μg/ml after which 0.25 ml of α-amylase solution (0.5 mg/ml) was added and pre-incubated at 25 °C for 5 min, followed by addition of 20 µl of 1% soluble starch, the tubes were then incubated at 37 °C for 30 min, the reaction was terminated by adding 0.5 ml of 3,5-dinitrosalicylic acid (DNS reagent). The reaction mixture was boiled for 10 min and cooled at room temperature, 5 ml distilled water was added, and the absorbance was recorded at 540 nm (Khanal and Patil 2020a, b); the experiment was performed in triplicates and percentage inhibition was calculated using the following formula:

Inhibitory activity%=(1-As/Ac)×100,

where “Ac” and “As” are the absorbance of control and sample respectively.

Drug-likeness score and probable adverse effect of flavonoids

The drug-likeness score of the flavonoids present in the fruit pulp of F. elephantum was calculated using MolSoft (Chuprina et al. 2010) (https://www.molsoft.com/mprop/) server by querying the InChI Key of the flavonoid bioactive; Further, the adverse effect of the same was predicted using ADVERPred (Ivanov et al. 2018) server (http://www.way2drug.com/adverpred/).

In silico molecular docking

Ligand preparation

The ligand molecules were sketched from Marvin sketch and saved in .pdbqt format using autodock4.0 before that energy was minimized by mmff94 force field (Halgren 1996). Acarbose was taken as a positive control (Agarwal and Gupta 2016).

Target preparation and molecular docking

The α-amylase crystallographic protein structure was retrieved from RCSB (Berman et al. 2003) protein databank (PDB: 5VA9). The protein was visualized in a Ramachandran plot to assess the distributed amino acid residues using PROCHECK (https://servicesn.mbi.ucla.edu/PROCHECK/). Further, the preparation of protein structure was done by removing the heteroatoms, water molecules via Discovery studio 2019 (Systèmes 2019) to avoid interference during docking and was saved in .pdb format. Molecular docking was performed via Autodock4.0 by applying the Lamarckian Genetic Algorithm (SR and VA 2018), upon completion, ten different poses were obtained; the pose possessing the lowest binding energy was visualized for its ligand–protein interaction using discovery studio 2019.

Results

Identification of flavonoids as α-amylase inhibitors

Four bio-actives were identified as flavonoids from a total of 25 bio-actives (Murthy and Bapat 2019). Further, confirming by comparing pre-defined structural skeletons of flavone compounds with identified bio-actives. The name of bioactive, PubChem CID and InChI key has been summarized in Table 1 and the chemical structure of flavonoids has been represented in Fig. 1.

Table 1.

Name, PubChem CID, and InChI Key of flavonoids present in the plant Feronia elephantum

S. No. Flavonoid PubChem CID InChI Key
1 Saponarin 441381 HGUVPEBGCAVWID-KETMJRJWSA-N
2 Vitexin 5280441 QMIYFMUDAFLECV-ZDPVKSLXSA-N
3 Gallocatechin 65084 XMOCLSLCDHWDHP-SWLSCSKDSA-N
4 5,4-dihydroxy 3–3(3-methyl-but-2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside Not available QMIYFMUDAFLECV-ZDPVKSLXSA-N
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Fig. 1.

Fig. 1

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Chemical structure of flavonoids present in fruit pulp of Feronia elephantum a Saponarin, b vitexin, c Gallocatechin, d 5,4-dihydroxy3-3(3-methyl-but-2-enyl) 3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside

In-vitro α-amylase inhibitory activity

The test sample of concentration 100 µg/ml, showed 47.22 ± 1.53 percentage inhibition of α-amylase as compared to standard acarbose at same concentration displayed 73.82 ± 0.93 percentage inhibition of α-amylase (Table 2).

Table 2.

Percentage inhibition of α-amylasse

Concentration (µg/ml) Percent inhibition
Flavonoid rich fraction of Feronia elephantum 100 47.22 ± 1.53
Acarbose* 100 73.82 ± 0.93
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Drug-likeness and predicted adverse effects

The InChI key of individual flavonoids was used to predict the drug-likeness score and probable adverse effect; Three flavonoids saponarin, vitexin, and 5,4-dihydroxye3-3(3-methyl-but-2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside were predicted to possess a positive drug-likeness score of 0.29, 0.60, and 0.76 respectively. Table 3 summarizes the molecular formula, molecular weight, number of hydrogen bond acceptors, and number of hydrogen bond donors, MolLog P, MolLog S, and the drug-likeness score of flavonoids. Further, two flavonoids [5,4-dihydroxye3-3(3-methyl-but-2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside and vitexin were predicted to possess nephrotoxicity as an adverse effect with pharmacological activity of 0.510 and 0.388 respectively. Table 4 summarizes the probable adverse effect of flavonoids with their pharmacological activity and pharmacological inactivity.

Table 3.

Drug-likeness score of flavonoids identified from the fruit pulp of Feronia elephantum

Flavonoids Molecular formula Molecular weight (Dalton) NHBA NHBD MolLogP MolLogS (Log(moles/L) DLS
Saponarin C15H15NO3 257.11 3 1 2.68 − 2.84 0.29
Vitexin C21H20O10 432.4 10 7 0.77 − 1.81 0.60
Gallocatechin C15H14O7 306.07 7 6 0.26 − 0.91 − 0.04
5,4-dihydroxy3-3(3-methyl-but2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside C29H34O11 558.21 11 6 2.95 − 2.88 0.76
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NHBA number of hydrogen bond acceptors, NHBD number of hydrogen bond donors, DLS drug-likeness score

Table 4.

Adverse effect of flavonoids identified from the fruit pulp of Feronia elephantum

Sr. No. Flavonoids Adverse effects Pa Pi
1 Vitexin Nephrotoxicity 0.510 0.047
2 5,4-dihydroxy3-(3-methyl-but-2-enyl) 3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside Nephrotoxicity 0.388 0.092
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Pa pharmacological activity, Pi pharmacological inactivity

In-Silico molecular docking

Molecular docking was performed via Autodock4.0 by creating a grid box centered to the protein, vitexin was predicted to possess the highest binding affinity (binding energy i.e. − 7.98 kcal/mol) with an inhibition constant of 1.41 µm and three hydrogen bond interactions i.e. Asp411, Asn408, and Gln441. The binding affinity, hydrogen bond interaction, pi bond interactions have been summarized in Table 5. Figure 2 represents the 2D and 3D interaction of vitexin and standard acarbose with target α-amylase.

Table 5.

Molecular docking result of flavonoids from Feronia elephantum with α-amylase

Flavonoids Binding affinity (Kcal/mol) Inhibition constant (uM) Number of hydrogen bonds Number of hydrogen residues Pi-bonds Number of pi-bond residues
Saponarin − 4.56 457.15 5 Thr71, Thr114, Arg56 1 Ala50
Vitexin − 7.98 1.41 4 Asp411, Asn408, Gln441 0 Not present
Gallocatechin − 6.87 9.25 4 Asn364, Asn362, Arg343 2 Pro361, Val358
5,4-dihydroxye3-(3-methyl-but-2-enyl) 3,5,6-trimethoxy-flavone-7-O-b-d-glucopyranoside − 6.17 29.88 5 Arg252, Ser289, Glu282 1 Pro332
Acarbose* − 5.24 144.24 9 Arg195, Glu233, Ala198, His299, Asp300, Trp89, Val354 1 Trp59
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*Gold standard in the inhibition of α-amylase

Fig. 2:

Fig. 2:

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2D and 3D Interaction of A vitexin and B acarbose with target α-amylase

Discussion

Postprandial hyperglycemia (PPHG), a condition wherein there is a rise of blood glucose levels through hydrolysis of carbohydrates, catalyzed by enzymes i.e. α-amylase and α-glucosidase (Tayab et al. 2021), the pancreatic α-amylase specifically hydrolyze α-1,4-glycosidic bond of starch to yield maltose and glucose, these reactions which occur in the small intestine, eventually play a vital role in the pathogenesis of diabetes mellitus (Goff et al. 2018). The metabolites formed during PPHG are an independent risk factor for the development of cardiovascular complications. Therefore, inhibition of these enzymes results in a massive reduction of PPHG blood levels and its associated risk factors (Wu et al. 2014). System biology tools help in the prediction of possible mechanisms of how the drug may act, its binding affinity, and its pose at which it binds providing a prophecy for the investigator to investigate key aspects of the study (Duyu et al. 2020; Dwivedi et al. 2021a, b).

Hence, the present study was aimed to investigate whether the flavonoids present in F.elephantum can be used to inhibit the α-amylase enzyme which is a major catalytic enzyme involved in the pathogenesis of PPHG. Since flavonoids have been reported to possess certain anti-diabetic properties but the mechanism of inhibition of α-amylase by flavonoids present in F. elephantum fruit extract has not been yet demonstrated (Al-Ishaq et al. 2019). Therefore, the flavonoid-rich fraction of this plant was further evaluated for α-amylase inhibition activity and is reported that at 100 µg/ml concentration to inhibit 47.22 ± 1.53 percent of α-amylase (Fig. 3).

Fig. 3.

Fig. 3

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A 3D structure, B Ramachandran plot of α-amylase

Molecular docking can predict crucial information regarding the binding properties of the drug molecule with a specific target and also helps in the prediction of the best pose at which the ligand may bind with the target (Khanal et al. 2021; Patil et al. 2021; Dwivedi and Rasal 2020). Further, to evaluate the efficiency of flavonoids, molecular docking was carried out using autodock4.0 and it was predicted that vitexin possess the highest binding affinity (binding energy − 7.98 kcal/mol) with an inhibition constant of 1.41 µM, but hydrogen bond interaction was observed to be highest for acarbose i.e. 7 (Arg195, Glu233, Ala198, His299, Asp300, Trp89, Val354). The oral bioavailability of these flavonoids was predicted via drug-likeness score and it was predicted that 5,4-dihydroxye3-3(3-methyl-but-2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside violates “Lipinski rule of 5” yet it shows the highest drug-likeness score along with this vitexin showed the second-highest drug-likeness score with fewer violations, thus it can be stated that vitexin may possess good oral bioavailability; Likewise, vitexin was predicted to possess the highest binding affinity indicating it to be a major flavonoid responsible for the α-amylase inhibitory activity. Finally, two flavonoids 5,4-dihydroxye3-3(3-methyl-but-2-enyl)3,5,6-trimethoxy-flavone-7-O-β-d-glucopyranoside and vitexin were predicted for the probable adverse effects of nephrotoxicity with Pa > 0.7 Thus, we confirmed that the flavonoids present in the fruit extract F. elephantum contains certain α-amylase inhibitory properties which need to be further validated via in-vivo protocols.

Conclusion and future prospectus

The present study aimed to demonstrate the anti-diabetic activity of F. elephantum flavonoids rich fraction via in-vitro and in-silico α-amylase inhibition. In-silico studies predicted flavonoids to possess a potent binding affinity with α-amylase as compared to standard acarbose indicating flavonoids to be potent α-amylase inhibitors. Our results suggested that vitexin may act as one of the lead molecules involved in the inhibition α-amylase, it is therefore concluded that vitexin can be a valuable agent for anti-diabetic therapy, by proposing the vitexin rich functional food to diabetic patients may help to lower the blood sugar. However, predictions have been made through computer aids and a small application of in-vitro studies, further experimental procedures are required to validate the possible outcomes.

Acknowledgements

All the authors of this manuscript are thankful to Principal. KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research (KAHER) for his support.

Funding

This work did not receive any funds from any national or international agencies.

Declarations

Conflict of interest

All the authors of this manuscript have no conflict of interest in any financial and non-financial way.

Ethical statement

This work did not include any animals or human participants.

Footnotes

Publisher's Note

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

Saikiran Kulkarni and Prarambh Dwivedi contributed equally to this work.

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