Study of molecular docking to detect antihypertensive ... · molecular docking to predict natural...

Available online at www.worldscientificnews.com

( Received 27 August 2018; Accepted 12 September 2018; Date of Publication 13 September 2018 )

WSN 110 (2018) 42-55 EISSN 2392-2192

Study of molecular docking to detect antihypertensive phytochemicals of Oxalis

corniculata Linn. against angiotensin converting enzyme

Satinath Mondal1, Partha Talukdar2,* and Tarit Kumar Mondal1

1Radhanath Homeo Hall, Rupdaypur, Panskura, Purba Medinipur, West Bengal, India

2Department of Botany, Serampore College, Serampore, University of Calcutta, William Carey Road Hooghly, West Bengal – 712201, India

*E-mail address: [email protected]

*Phone: +919231531769

ABSTRACT

The locally available medicinal plant, Oxalis corniculata Linn. is a common weed and used by

villagers to prevent several diseases. The objective of the present study was to detect receptor-ligand

binding energy and interaction through molecular docking for phytocompounds established in O.

corniculata against angiotensin converting enzyme (ACE) (PDB ID: 1O86). Molecular docking was

performed by using PyRx (Version 0.8) for the structure-based virtual screening and visualized the

interaction in the MGL tool (Version 1.5.6). Among 16 phytochemicals and 4 antihypertensive

synthetic drugs, highest binding energy value (Kcal/mol) was obtained in Apigenin (-8.9) compared to

other four drugs such as Lisinopril (-7.7), Temocapril (-7.6), Enalapril (-7.5) and Captopril (-5.7). The

binding interaction of target protein with this phytocompound found binding at active site may be

showed as competitive inhibitor. In conclusion, phytoligand Apigenin can be a suitable lead

compound for antihypertensive agent and an alternative of synthetic drug as per binding energy value

and molecular interaction. It is suggesting further pharmacological and toxicological assay with this

phytoligand after extraction from O. corniculata to validate the present results of computational

screening.

http://www.worldscientificnews.com/

World Scientific News 110 (2018) 42-55

-43-

Keywords: Oxalis corniculata, Antihypertensive phytochemicals, Angiotensin-converting enzyme,

Receptor-ligand binding, Molecular docking and interaction

1. INTRODUCTION

The term hypertension means high blood pressure in the arteries, which is a global

burden (Whelton, 1994; Kearney et al., 2005). The treatment is done by several synthetic

compounds such as captopril, enalapril, lisinopril, temocapril, etc. to regulate the blood

pressure along with the prevention of myocardial infarction, cardiovascular diseases, etc.

(Chang et al., 2015). An important enzyme namely angiotensin-I converting enzyme (ACE)

plays vital role in the regulation of blood pressure or hypertension (Kumar et al. 2010). It was

known that the blood pressure occurred due to conversion of angiotensin I into angiotensin II

(Natesh et al., 2003; Akif et al., 2010; Kumar et al., 2010; Nishibori et al., 2012; Muthia et al.,

2017). Therefore, prevention of high blood pressure, it is required to inhibit ACE activity

(Chusman and Ondetti, 1999). Generally, synthetic drugs for ACE inhibitors may pose side

effects to human and the researchers have prioritized natural products from medicinal plants,

which have no side effects, cost-effective and low dose with better therapeutic improvement

(Muthia et al., 2017).

In the research of last decade, ACE I to II conversion is basically by cleaving the

carboxy terminal His-Leu dipeptide to vasopressor octapeptide, which is the main causative

factor for hypertension, heart failure, myocardial infarction and diabetic nephropathy (Natesh

et al., 2003). On the other hand, the causative factor for ACE I to II conversion is well-known

and still several inhibitors are found with side effects of other pathways (Akif et al., 2010).

Among several medicinal plants of India and other parts of the globe are used to prevent

blood pressure or hypertension as per traditional knowledge (Tabassum and Ahmad, 2011;

Tripathi et al., 2013; Baharvand-Ahmadi et al., 2016). But the medicinal plant, locally known

as Amrul sak (Oxalis corniculata L.) has potent medicinal properties and inhabited profusely

and wild in nature (David et al., 1996; Mary et al., 2001; Basumatary et al., 2004). The usage

of extracts of medicinal plants by traditional knowledge for the prevention of diseases is

believed as safe, low cost and easily available (Srikanth et al., 2012; Muthia et al., 2017) but

molecular docking to predict natural compounds of O. corniculata for the inhibition of ACE

is lacking. Moreover, molecular docking technique is used within a few hours to predict the

interaction between macromolecule (protein) with small molecules (ligands) at molecular

level (Morris and Lim-Wilby, 2008).

The objective of the present study was to detect suitable receptor-ligand binding energy

and molecular interaction through molecular docking approach for phytocompounds

established in O. corniculata against angiotensin converting enzyme (ACE) (PDB ID: 1O86).

2. MATERIALS AND METHODS

2. 1. Selection of target proteins as receptors

The three-dimensional (3D) crystal structures of two angiotensin converting enzyme

(ACE) in complex with lisinopril were retrieved from European Protein Data Bank


-44-

(www.ebi.ac.uk) and the structure has been developed by researcher (Natesh et al., 2003),

having PDB code 1O86 (Figure 1).

Fig. 1. Three-dimensional (3D) ribbon structure of ACE [(PDB ID: 1O86) attached with line

structure of Lisinopril (LPR) at 702 position along with ball structure green colour chlorine

atoms at 703 and 704 position and blue colour zinc atom at 701 position]

2. 2. Selection of phytochemicals as ligands

According to Srikanth et al. (2012), 26 types of phytochemicals from the literature study

on Oxalis corniculata (Figure 2) and 4 established synthetic drugs were selected. These are β-

sitosterol, betulin, 4-hydroxybenzoic acid, ethyl gallate, methoxyflavones, apigenin, 7-O-β-D-

glucopyranoside, iso vitexine and vitexine-2”-O-β-D-glucopyrunoside, palmitic acid, oleic

acid, linoleic acid, linolenic acid, stearic acid, tartaric acid, citric acid, calcium oxalate, 4'-

OMe vitexin, 4'-OMeiso-vitexin and 3',4'-diOMe orientin, 3',4'-diOMe quercetin, p-

hydroxybenzoic acid, vanillic acid and syringic acid, 6-C-glucosyl luteolin (isoorientin), 6-C-

glucosylapigenin (isovitexin) and isovitexin 7- methylether (sertisin) and synthetic drugs

captopril, enalapril, lisinopril and temocapril respectively (Table 1).

Among 26 phytoligands, only 16 were used due to availability of chemical IDs. The

chemical ID of each ligand was taken from PubChem database

(https://pubchem.ncbi.nlm.nih.gov/). 3-D structure of each ligand is exhibited in Fig 3A-T

obtained through CORINA online server (www.mn-am.com/online_demos /corina_demo)

after incorporating SMILES string in the appropriate place.


-45-

Fig. 2. The plant species Oxalis corniculata

2. 3. Molecular docking and interaction study

The docking was carried out by a virtual screening method through PyRx software

(Virtual Screening Tool, Ver 0.8) developed by Trott and Olson (2010). The molecular

docking was visualized the output .pdbqt file by using MGL tool, developed by The Scripps

Research Institute (Morris et al., 1998; Morris and Lim-Wilby, 2008) and the results of three-

dimensional structure were rendered by using MGL Tools. Docking of ligands from 16

phytochemicals as per available pdb files and 4 synthetic drugs as pdb file against ACE (PDB

IDs: 1O86) were analysed to detect suitable binding energy value.

The phytoconstituents and synthetic drugs (ligands) with ACE (receptor) to identify the

residues involved in each case of receptor-ligand interactions. The docking site on this target

protein was expressed by forming a grid box with the dimensions of X: 62.7765, Y: 73.0057

and Z: 67.4844 Å, with a grid spacing of 0.375 Å, centered on X: 40.5229, Y: 37.2692 and Z:

43.6492 Å. The present tool predicts docking result by obtaining energy value for each ligand.

Finally, all the test compounds analysed to detect binding position and energy value.

The resultant structural complexes of the individual ligand/receptor binding were finally

observed in AutoDoc Vina software (Morris et al., 1998), to determine some specific contacts

between the atoms of the test compounds and amino acids of ACS protein.


-46-

Table 1. Established phytochemicals of Oxalis corniculata

Sl. No. Ligands Chemical ID

Phytochemicals

1. β-sitosterol 222284

2. Betulin 72326

3. 4-hydroxybenzoic acid NF

4. Ethyl gallate 13250

5. Methoxyflavones 146013

6. Apigenin 5280443

7. 7-O-β-D-glucopyranoside NF

8. Isovitexine 162350

9. Vitexine-2”- O- beta – D- glucopyrunoside NF

10. Palmitic acid 985

11. Oleic acid 445639

12. Linoleic acid 5280450

13. Linolenic acid 5280934

14. Tartaric acid 875

15. Citric acid 311

16. Calcium oxalate 33005

17. 4'-OMe vitexin NF

18. 4'-OMeiso-vitexin NF

19. 3',4'-diOMe orientin NF

20. 3',4'-diOMe quercetin NF

21. P-hydroxybenzoic acid 135

22. Vanillic acid 8468

23. Syringic acid 10742

24. 6-C-glucosyl luteolin NF

25. 6-C-glucosyl apigenin NF

26. Isovitexin 7- methylether NF

Synthetic drugs

1. Captopril 44093

2. Enalapril 5388962

3. Lisinopril 5362119

4. Temocapril 443874

NF = Not found in PubChem database


-47-

A B

C D E

F

G

H

I J


-48-

K L M

N O P

Q R

S T

Fig. 3. 3-D structure of phytocompounds and synthetic compounds (A = β-sitosterol;

B = Betulin; C = Ethyl gallate; D = Methoxyflavones; E = Apigenin; F = Isovitexine;

G = Palmitic acid; H = Oleic acid; I = Linoleic Acid; J = Linolenic Acid; K = Tartaric acid;

L = Citric acid; M = Calcium oxalate; N = P-hydroxybenzoic acid; O = Vanilic acid;

P = Syringic acid; Q = Captopril; R = Enalapril; S = Lisinopril; T = Temocapril)


-49-

3. RESULTS AND DISCUSSION

Present computational screening through a molecular docking approach indicates that

favourable binding energy (Kcal/mol) was observed, and highest binding energy value was

observed in Apigenin and Isovitexine (-8.9), followed by β-sitosterol (-8.7), Betulin (-8.2),

Methoxyflavones (-7.9), P-hydroxybenzoic acid and syringic acid (-6.5), Linolenic acid (-

6.3), Ethyl gallate and Vanillic acid (-6.2), Linoleic acid (-6.1), Palmitic acid (-6.0), Oleic

acid (-5.6), Citric acid (-5.2), Tartaric acid (-4.9) and lowest value was obtained in Calcium

oxalate (-1.4) among established secondary metabolites of O. corniculata in comparison with

four synthetic drugs Lisinopril, Temocapril, Enalapril and Captopril obtained -7.7, -7.6, -7.5

and -5.7 Kcal/mol binding energy values respectively (Table 1).

Table 2. Binding energy values of phytochemicals of Oxalis corniculate and synthetic drugs

against ACE receptor (PDB ID: 1O86)

Sl. No. Ligands Binding energy

(Kcal/mol)

Phytochemicals

1. Apigenin -8.9

2. Isovitexine -8.9

3. β-sitosterol -8.7

4. Betulin -8.2

5. Methoxyflavones -7.9

6. P-hydroxybenzoic acid -6.5

7. Syringic acid -6.5

8. Linolenic acid -6.3

8. Ethyl gallate -6.2

9. Vanillic acid -6.2

10. Linoleic acid -6.1

11. Palmitic acid -6.0

12. Oleic acid -5.6

13. Citric acid -5.2

14. Tartaric acid -4.9

15. Calcium oxalate -1.4

Synthetic drugs

1. Lisinopril -7.7

2. Temocapril -7.6

3. Enalapril -7.5

4. Captopril -5.7


-50-

A a

b B

C c


-51-

Fig. 4. Docking pose (ball and stick structure) along with attached an inhibitory molecule

(line structure) and ball structure of two green colour chlorine atoms and blue colour zinc atom

(A = Apigenin; B = Lisinopril; C = Temocapril; D = Enalapril) and ligand binding interaction

with residues (a = Apigenin; b = Lisinopril; c = Temocapril; d = Enalapril; green dotted

line = hydrogen bonding)

Figure 4 A-D and a-d exhibited binding pose and interaction, where all four compounds

(one phytoligand and three synthetic ligands) found in the active site of target receptor (PDB

ID: 1O86). The binding of apigenin was observed in the receptor with one hydrogen bonding

connected with ALA356 and the attached amino acid residues were observed HIS387,

HIS410, GLY404 and ARG522 respectively. The binding of Lisinopril was observed in the

receptor without any hydrogen bonding but contact residues were found as ARG522,

TYR394, HIS387, PHE391, ALA356, TRP367, ASP353, TYR360 and ASN66 while

Temocapril obtained two hydrogen bonding connected with ASP358 and contact residues viz.

PHE39, TYR394, ASN66 respectively and Enalapril were observed in the receptor along with

contact residues such as ARG522, GLY404, GLU403, HIS387 and ALA356 without any

hydrogen bonding.

In Figure 5, the superimposed docking poses and interactions with amino acid residues

were obtained suitable for one phytyoligand as Apigenin and three synthetic ligands such as

Lisinopril, Temocapril, Enalapril found in the active site of target receptor (PDB ID: 1O86).

In the present docking and interaction study, it was observed that the flavonoid

Apigenin and Isovitexine showed highest binding energy and lowest score but suitable

binding at the active site as inhibitor was observed only for apigenin for ACE-lisinopril

receptor. It has been documented that few flavonoids like Apigenin, Naringenin, Quercetin

and Kaempferol are suitable inhibitor for ACEs by Hafeez et al. (2014).

d D


-52-

Fig. 5. Docking pose (ball and stick structure) along with attached an inhibitory molecule

(line structure) and ball structure of two green colour chlorine atoms and blue colour zinc atom

(Apigenin = yellow; Lisinopril = magenta; Temocapril = orange; Enalapril = white) and

ligand binding interaction with residues (Apigenin = yellow; Lisinopril = magenta;

Temocapril = orange; Enalapril = white; green dotted line = hydrogen bonding)


-53-

Some contradictory observations were found in the present study for apigenin ligand

that binding with one hydrogen bond connected with ALA356 and the attached amino acid

residues were observed HIS387, HIS410, GLY404 and ARG522 but in earlier study by

Hafeez et al. (2014) the binding of apigenin with the amino acid residues of the active site of

ACE-lisinopril complex connected with amino acids GLU384, TYR523, HIS353, and

ALA354 with the two hydrogen bonds connected with GLN281 and LYS511. In present

results, 4 compounds (1 phytoligand and three synthetic ligands) did not show any connection

with zinc atom in the active site, which has a close similarity with earlier work done by

Shukor et al. (2013) for few flavonoid phytochemicals.

Although, researcher documented in experimental study that the pure compounds of

flavonoids showed potent antihypertensive properties on ACE enzyme derived from rabbit

lung (Shukor et al., 2013). Their study supports the present computation screening in which

apigenin has higher binding energy value and interaction with amino acids in the active site. It

is suggesting further in vivo experiment with the extract of each phytochemical of O.

corniculata on ACE enzyme to validate present predictive results.

4. CONCLUSIONS

It is concluded from the above molecular docking and interaction study, phytoligand

Apigenin can be a lead compound and alternative of synthetic antihypertensive drug as per

binding energy value and interaction of competitive inhibition. According to Muthia et al.

(2017) plant derived natural chemical can be suitable as lead compound to prevent the side

effects of synthetic drug. This present predictive study is suggesting functional and

toxicological assay with this phytoligand after isolation from O. corniculata on ACE receptor.

Acknowledgement

The authors convey thanks to the developers of present software used in the predictive study, data bank for

protein and phytochemicals. The authors are thankful to Dr. Balaram Jana, National Teacher and President

Homeopathic Research Society of India for providing valuable suggestions and continuous inspiration to conduct

the present study.

References

[1] Whelton PK. Epidemiology of hypertension. Lancet 344 (1994) 101-106.

[2] Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of

hypertension: analysis of worldwide data. Lancet 365 (2005) 217-223.

[3] Chang C-H, Lin J-W, Caffrey JL, Wu L-C, Lai M-S. Different angiotensin-converting

enzyme inhibitors and the associations with overall and cause-specific mortalities in

patients with hypertension. American Journal of Hypertension 28(6) (2015) 823-830.

[4] Kumar R, Sharma R, Bairwa, K, Roy RK, Kumar A, Baruwa A. Modern Development

in ACE inhibitors. Der Pharmacia Lettre 2(3) (2010) 388-419.


-54-

[5] Nishibori N, Takefumi S, Takara H, Reina K, Manami S, Mari I, Kyoji M, Song H.

Inhibition of angiotensin i-converting enzyme (ACE-I) by aqueous extracts prepared

from edible and non-edible parts of lotus root. Phytopharmacology 3(2) (2012) 309-

318.

[6] Natesh R, Schwager SLU, Sturrock ED, Acharya KR. Crystal structure of the human

angiotensin-converting enzyme-lisinopril complex. Nature 421(6922) (2003) 551-554.

[7] [7] Muthia R, Suganda AG, Sukandar EY. Angiotensin-I converting enzyme (ACE)

inhibitory activity of several Indonesian medicinal plants. Research Journal of

Pharmaceutical, Biological and Chemical Sciences 8(1S) (2017 Suppl.) 192-199.

[8] Chusman DW, Ondetti MA. Design of Angiotensin Converting Enzyme Inhibitors.

Nature medicine 5(10) (1999) 1110-1112.

[9] Tabassum N, Ahmad F. Role of natural herbs in the treatment of hypertension.

Pharmacognosy Reviews 5(9) (2011) 30-40 doi:10.4103/0973-7847.79097.

[10] Tripathi S, Ray S, Mondal AK, Verm NK. Rare ethno medicinal plants of south West

Bengal, India with their different medicinal uses: Needs conservation. International

Journal of Life Sciences Biotechnology and Pharma Research 2(2) (2013) 114-122.

[11] Baharvand-Ahmadi B, Bahmani M, Tajeddini P, Rafieian-Kopaei M, Naghdi N. An

ethnobotanical study of medicinal plants administered for the treatment of hypertension.

Journal of Renal Injury Prevention 5(3) (2016) 123-128.

[12] Hall DW, Vandiver VV, Sellers BA. Creeping Wood Sorrel, Oxalis corniculata L.

Southern Yellow Wood Sorrel, Oxalis florida Salisb. SP 37, Florida Cooperative

Extension Service, Institute of Food and Agricultural Sciences, University of Florida

(1996) 01-02.

[13] Mary Z, Vasantha Kumar KG. Pasupathy S, Bikshapathi. T. Pharmacognostical studies

on changeri Oxalis corniculata Linn. (oxalidaceae). Ancient Science of Life 2001; 21(2);

1-8

[14] Mary Z, Kumar KGV, Pasupathy S, Bikshapathi T. Pharmacognostical studies on

Changeri Oxalis corniculata Linn. (oxalidaceae). Ancient Science of Life 21(2) (2001)

120-127.

[15] Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with

a new scoring function, efficient optimization and multithreading. Journal of

Computational Chemistry 31 (2010) 455-461.

[16] Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ.

Automated docking using a Lamarckian genetic algorithm and an empirical binding free

energy function. Journal of Computational Chemistry 19 (1998) 1639-1662.

[17] Morris GM, Lim-Wilby M. Molecular docking. Methods in Molecular Biology 443

(2008) 365-382, doi: 10.1007/978-1-59745-177-2_19

[18] Hafeez A, Askari H, Khan N, Akram M, Hanif S, Urooj N. Molecular modeling of plant

flavonoids as angiotensin converting enzyme (ACE) inhibitors in hypertension: A

docking study. World Journal of Pharmaceutical Sciences 2(5) (2014) 499-506.


-55-

[19] Shukor NA, Camp JV, Gonzales GB, Staljanssens D, Struijs K, Zotti MJ, Raes K,

Smagghe G. Angiotensin-converting enzyme inhibitory effects by plant phenolic

compounds: A study of structure activity relationships. Journal of Agricultural and

Food Chemistry 61 (2013) 11832-11839.

Study of molecular docking to detect antihypertensive ... · molecular docking to predict natural...

Documents

Transcript of Study of molecular docking to detect antihypertensive ... · molecular docking to predict natural...