Molecular Docking and Admet Studies of Nigella sativa Plant against Osteoporosis

 

Sonal P. Kumbhar1, Pratiksha A. Satpute2, Akash Thombare1, Shalini Shinde1, N. B. Chougule3

1Assistant Professor, Ashokrao Mane Institute of Pharmacy, Ambap, 416112.

2Student, Ashokrao Mane Institute of Pharmacy, Ambap. 416112.

3Principal5, Ashokrao Mane Institute of Pharmacy, Ambap. 416112.

2Assistant Professor, Womens College of Pharmacy, Peth-Vadgaon 416112.

*Corresponding Author E-mail: sonalkumbhar05@gmail.com, pratikshasatpute22@gmail.com

 

ABSTRACT:

Utilising docking of molecules and ADMET research, this investigation explores the possibility of Nigella sativa, or black seed, as a treatment for osteoporosis. Osteoporosis is a huge global public health concern since it considerably raises the menace of fractures and causes a diminution in bone density. Despite existing treatments, there remains a need for novel therapeutic agents with improved efficacy and safety profiles. Nigella sativa, renowned for its diverse pharmacological properties, emerges as a promising candidate for osteoporosis management. Through molecular docking analysis, the interaction between bioactive compounds present in Nigella sativa and key osteoporosis-related targets, like activator ofkappa-Β ligand receptor and osteoprotegerin was explored. The results reveal potential binding affinities and binding modes, suggesting the ability of Nigella sativa constituents to modulate osteoporosis-related pathways. Additionally, ADMET predictions provide valuable insights into the pharmacokinetic and toxicity profiles of Nigella sativa compounds.

 

KEYWORDS: Oteoporosis, Toxicity, Osteoprotegerin, Pharmacological Properties, Distribution

 

 

INTRODUCTION:

Osteoporosis is a complaint that deteriorates bones and increases their susceptibility to fractures due to its symptoms, which include decreased bone mass, tissue breakdown and disturbance of bone microarchitecture.1 Sir Astley Paston Cooper, an anatomist and surgeon from Britain, made a comment in 1822 about the correlation between defective bones and fractures.

 

 

 

In 1835, the term "osteoporosis" was initially used by French surgeon and pathologist Jean Lobstein to describe a disorder characterised by blue-grey sclera, likely osteogenesis imperfecta type I. After women's ovaries stopped producing eggs, Fuller Albright documented instances of spinal fractures in 1941. These women were able to stop losing height and had an improved calcium balance after receiving oestrogen medication.2 in Over 200 million people around the world are believed to have suffered from osteoporotic hip fractures3 The risk of osteoporotic fractures is around 30% for men and 40% for postmenopausal women; In the US and Europe, 30% of women suffer from osteoporosis.4-6

 

Similar to hypertension, osteoporosis frequently has a protracted latent period before any symptoms or consequences manifest. The majority of adverse events are compression cracks of proximal femurs, spinal columns, humeri, ribs, and distal radiuses. One of the most noticeable symptoms of osteoporosis is the development of pathologic fractures7,8. Fractures are communal in ageing and those with osteoporosis because of the increased risk of falling.9,10 Recent studies on the topic of senior falls have found a plethora of risk factors. Common among this demographic are illnesses of the nervous system and musculoskeletal system, as well as cardiovascular disease and vision impairments, all of which have intrinsic origins. Sedative and prescription drug abuse, poor illumination, clutter, and other obstacles (such as stairs, curbs, and scatter rugs) all contribute to an individual's extrinsic fall risk.11-14

 

The elderly have a substantially improvedthreat of fracture associated to younger people, regardless of bone mineral density test.15 Hip fractures in particular are more common in older adults, particularly those over the age of 70, and this trend holds true around the globe for both sexes.21,22 Fracture risk increases with age for a number of reasons, including a deterioration in proximal femoral bone mineral density, an increase in falls with advancing age, and an association with more chronic health conditions in the elderly. Hormonal variables - variations between sexes Peak bone mass is lesser in women than in men. In US and Europe, occurrence of hip fractures in women is approximately double that in males at any age. This is due to the fact that women experience greater bone loss after menopause and are more prone to falls than men. Another interesting fact is that women have a higher rate of hip fractures than men do. This could be because women incline to livinglengthier than men. According to majority of experts16–19 proportion of hip fractures in women is twice that in men over the age of 65. Factors that raise the likelihood of fractures include: a predisposition to fragility fractures, a lack of bone mineral density, an underweight patient, anticonvulsants, rheumatoid arthritis, corticosteroids, loop diuretics, and a history of falls.20-21

 

New, non-pharmaceutical methods for bone maintenance and osteoporosis prevention and therapy have emerged, and they show promise. Using an animal model of postmenopausal osteoporosis, researchers have examined the effects of many medicinal herbs, including soy, blueberries, Achyranthes bidentata, and Labisia pumila.22-23 Herbalists regularly use nigella sativa. Hak Jung Chou is the Chinese name, although other names include black cumin, habatus sauda, kalonji, and kalajeera.24 It bears delicate blue blossoms and reaches a maximum height of 30 cm. Nigella sativa seeds are employed in liquors and candies due to their strong bitter flavour25 The antioxidant, anti-inflammatory, antibacterial, anti-cancer, antifungal, and antiparasitic properties  of Nigella sativa have been uncovered through scientific investigations26–31 Thaymol, thymohydroquinone, thymoquinone, and dithymquinone are the major constituents of Nigella sativa seeds.32

 

Cathepsin K:

One of the most powerful proteases in the family of lysosomal cysteine proteases, cathepsin K (CatK) mediates bone resorption. At present, CatK is one of the most alluring targets for the development of drugs to combat osteoporosis. There is currently no FDA-approved drug for CatK, despite the fact that numerous pharmaceutical companies are engaged in the development of such drugs. Merck and Co.'s Odanacatib (ODN) is the sole contender among CatK inhibitors that showed promising results in Phase III clinical studies for treating postmenopausal osteoporosis.33,34

 

MATERIALS AND METHODS:

1.     Ligandcuration and preparation:

To identify phytoconstituents with known osteoporosis-related properties, we searched the scientific literature. From the NCBI PubChem database (pubchem.ncbi.nlm.nih.gov), ten (10) compounds' chemical structures were supplied in 3D SDF format and compared to cathespin k. All of the synthetic ligands were compressed into one SDF file using the Open Babel programme (openbabel.org) so that they could be easily included into the PyRx software.

 

2.     Protein Preparation:

Protein Data Bank (PDB ID:5TDI) was queried to obtain the Human Cathepsin K complex with the substrate (https://www.rcsb.org/). After receiving the data in PDB format, it was imported into BIOVIA Discovery Studio Visualizer 2021 v21.1.0.20298. The process included introducing polar hydrogens after removing water molecules and heteroatoms.

 

3.     Active Site Preparation:

Discovery Studio, the PDB, and the literature are anticipated to contain the active sites for 5TDI. For the PyRx software to cover the target protein binding site in its grid box configuration, the correct predicted amino acid residue needs to be selected. All of the proteins' ligand binding affinities were shown and recorded.

 

4.     Molecular Docking Studies:

The PyRx software version 0.8 was used to perform molecular docking simulations. One tool for virtual high-throughput screening of chemicals in contradiction of protein targets is PyRx, which makes use of molecular docking simulations. In order to determine which compounds are most likely to make a strong connection with a protein, it is necessary to calculate their binding energies in kcal/mol. We next loaded the produced and compressed 3D ligands in SDF format using PyRx's in-built OpenBabel graphical user interface. The conjugate gradient method, UFF, and a total of two hundred steps were employed to decrease energy. If the energy difference is more than the threshold, the update process will terminate after one step per mole. After that, in an effort to reduce energy usage (pdbqt), all ligands were transformed to AutoDock ligands. Importing the docked protein into PyRx and converting it to pdbqt followed. A degree of eight exhaustiveness was used when the docking simulation was executed. Among all the ligands tested, the one with the strongest binding tendency had the largest negative binding energy. BIOVIA Discovery Studio was used to show specific interactions of the optimal docking positions.

 

5.     Theoretical Prediction of ADMET Parameters:

We used the SMILES format to export the top-scoring compounds from the docking simulation to SwissADME then pkCSM web server.Bio availability and Toxicityof these compounds were then predicted using techniques like Lipinski's rule of five. Using the SwissADME online application, the properties of substances' ADME were computed. The Ipomoea Tricolour compounds used in the docking analysis were predicted to be drug-like using this computation. The planned drug qualities and the known drug ADME properties are the only comparisons made.

 

RESULT AND DISCUSSION:

Molecular Docking Simulations:

Molecular docking experiments were performed to identify Cathepsin k inhibitors from natural sources. The result indicates that certain compounds found in nature have higher binding energies than prescription drugs. The binding energies of the 10 compounds that are commonly used as anti-osteoporosis drugs are listed in the table below. The chemical composition of plant sources was discovered through IMPPAT, Wikipedia, and additional written records. Thymoquinone (TQ), a quinone component of N. sativa, has a molecular weight of -5.3kcal/mol. The study showed the 3D and 2D structures of carvacrol in relation to the cathepsin k protein (PDB ID: 5TDI). The interaction between Cathepsin K and the ATP-binding site of 5TDI is also shown in the picture. Alpha-thujene, thymol, t-anethol, beta-pinene, alpha-pinene, gamma-terpinene, thymohydroquinone, and P-cymene have better ligand-protein interactions and binding activities.


 

Table1:DockingandInteractions of 10Phytochemicalsagainstcathepsin k.

S. No.

Pub Chem ID

Binding Affinity (Kcal/mol)

Interacting Residue

Type of interaction

1

  10364

    -5.4

TRPA:188,ASNA:18,GLNA:19

Van Der Waals

GLYA:20

Conventional Hydrogen Bond

TRPA:184

Pi-Pi Stacked

2

10281

    -5.3

VALA:128,LYSA:214,ARGA:127,GLUA:112,ALAA:120,ARGA:123,ILEA:113,PROA:114,

Van Der Waals

ARGA:111

Conventional Hydrogen Bond

PHEA:212

Pi-Pi T Shaped

ALAA:124

Pi-Alkyl

3

6989

    -5.3

A:TRP:188,A:GLY:20,A:GLN:19

Van Der Waals

A:ASN:18

Conventional Hydrogen Bond

A:TRP:184

Pi-Pi Stacked

4

95779

     -5.3

ARGA:123,ILEA:113,PROA:114,GLUA:112,LYSA:214

Van Der Waals

ALAA:120,ARGA:111

Conventional Hydrogen Bond

PHEA:212

Pi-Pi T Shaped

ARGA:127,ALAA:124,VALA:128

Pi-Alkyl

5

637563

     -5.3

SERA:58, GLUA:59

Van Der Waals

ASNA:70

Conventional Hydrogen Bond

GLNA:73

Amide-Pi Stacked

TYRA:74,LYSA:77,VALA:57

Pi-Alkyl

 

 

Fig 1: 2D and 3D interactions of Carvacrol

 

Fig 2: 2D and 3D interactions of Thymoquinone

 

 

Fig 3: 2D and 3D interactions of Thymol

 

 

Fig 4:2D and 3D interactions of thymohydroquinone

 

 

Fig 5: 2D and 3D interactions of t- anethole

 

 

 

Drug like-ness and ADMET Prediction:

The acronym ADMET denotes the following processes in the fields of pharmacokinetics, pharmacology, and toxicology: ADMET. This method zeroes in on a compound's physiochemical, drug-like, and physicochemical features. The principle underlying ADMET is that designed for chemical to remain in effect when taken orally, it must be bioavailable, transported to target locations, metabolised effectively, eliminated after performance, and not negatively impact cells, tissues, or organs it comes into touch with. In this study, the ADMET test results were presented in tables. The best-performing medications and common inhibitors had their ADMET properties predicted using the web servers of SwissADME and pkCSM. The findings demonstrated that a number of compounds ran counter to Veber's, Ghose's, Egan's, Muegge's, and Lipinski's Rules of Five (RO5). Tables 2 and 3 provide the physiochemical properties that were acquired from the pkCSM web server.

 

 

Table 2: ADMET Properties of Phytochemicals by PkCSM

Sr.

No.

Pub Chem Id

Absorption

Distribution

Intestinal Absorption (Human)

P-Glyco protein Substrate

PGlyco protein Substrate I

P-Glyco

protein

Substrate II

VDss (Human)

BBB  Perme ability

CNS  Perme ability

Numeric (%absorbed)

Categorial

(Yes/No)

Categorial

(Yes/No)

Categorial

(Yes/No)

Numeric (logLkg-1)

Numeric (logBB)

Numeric (logPS)

1

10364

90.843

No

No

No

0.512

0.407

-1.664

2

10281

99.382

No

No

No

-2.026

0.326

-2.269

3

6989

90.843

No

No

No

0.512

0.407

-1.664

4

95779

90.669

Yes

No

No

0.315

0.117

-1.738

5

637563

95.592

No

No

No

0.343

0.429

-1.659

 

Table 2: Cont….

Sr.

No.

Pub Chem Id

Metabolism

Excretion

Toxicity

Substrate

Inhibitors

Total Clearance

AMES

Toxicity

CYP

2D6

3A4

1A2

2C19

2C9

2D6

3A 4

 

 

Categorial

(Yes/No)

Numeric

(logm Lmin-1kg-1)

Categorial (Yes/No)

1

10364

No

No

Yes

No

No

No

No

0.207

No

2

10281

No

No

No

No

No

No

No

0.225

No

3

6989

No

No

Yes

No

No

No

No

0.211

No

4

95779

No

No

Yes

No

No

No

No

0.24

No

5

637563

No

No

Yes

No

No

No

No

0.268

No

 

 

Table 3:Drug-Likenessproperties of phytochemicals by Swiss ADME.

Srno.

PubChem ID

MW

(g/mol)

M LogP

HBA

HBD

MR

TPSA

1

10364

150.22

2.24

1

1

48.01

20.23 Ų

2

10281

164.20

1.99

2

0

47.52

34.14Ų

3

6989

150.22

2.32

1

1

48.01

20.23Ų

4

95779

166.22

2.10

2

2

50.03

40.46Ų

5

637563

148.20

2.55

1

0

47.83

9.23 Ų

 

Table 3: Cont….

Srno.

n Rot

Lipinski'sRule(Ro5)

Veber's Rule

Ghose'sRule

Egan'sRule

Muegge'sRule

1

1

Yes

Yes

No

Yes

No

2

1

Yes

Yes

Yes

Yes

No

3

1

Yes

Yes

No

Yes

No

4

1

Yes

Yes

Yes

Yes

No

5

2

Yes

Yes

No

Yes

No

 

 

CONCLUSION:

Nigella sativa has demonstrated promise as a secure and reliable antiosteoporotic medication. To have a complete understanding of Nigella sativa's effects, additional research utilising other animal osteoporotic models is required. The best-performing chemicals, according to the findings of the molecular docking experiments conducted in this study, were beta-pinene, alpha-pinene, gamma-terpinene, alpha-thujene, p-cymene, thymol, carvacrol, and t-anethole. However, because of their ADMET characteristics, some of these compounds are worth examining further. Since their BBB and CNS values are low, indicating that they have limited access to the nervous system, they are deemed safe for use

 

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Received on 01.07.2024      Revised on 13.12.2024

Accepted on 08.04.2025      Published on 03.05.2025

Available online from May 05, 2025

Asian J. Pharm. Res. 2025; 15(2):121-126.

DOI: 10.52711/2231-5691.2025.00020

©Asian Pharma Press All Right Reserved

 

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