issn: international journal of novel …related to hypothyroidism, male infertility and female...

VOLUME 5 | NUMBER 3 | JUN | 2015 |42

Available online at www.ijntps.org | ISSN: 2277 – 2782 INTERNATIONAL JOURNAL OF NOVEL TRENDS IN PHARMACEUTICAL SCIENCES

Identification of insilico drugs and drug docking studies on

hypothyroidism and inferility disorders in human

Anusha CS1*

, Halidha Z1, Radha T

2 and Balaji M

3

1Post Graduate and Research Department of Zoology, Ethiraj College for Women, Chennai, Tamilnadu, India.

2Associate professor, Post Graduate and Research Department of Zoology, Ethiraj College for Women, Chennai,

Tamilnadu, India.

3Senior Bioinformatician, Akshaya Computational Medicine Pvt, Ltd., Chennai, Tamilnadu.

INTRODUCTION

Worldwide about one billion people are estimated

to be iodine deficient; however, it is unknown how

often this results in hypothyroidism [1]. In large

population-based studies in Western countries with

sufficient dietary iodine, 0.3–0.4% of the population

has overt hypothyroidism. A larger proportion, 4.3–

8.5%, has subclinical hypothyroidism [2]. Of people

with subclinical hypothyroidism, 80% have a TSH

level below the 10 mIU/l mark regarded as the

threshold for treatment [3]. Children with subclinical

hypothyroidism often return to normal thyroid

function, and a small proportion develops overt

hypothyroidism (as predicted by evolving antibody

and TSH levels, the presence of celiac disease, and

the presence of a goiter)[4].

Women are more likely to develop hypothyroidism

than men. In population-based studies, women

were seven times more likely than men to have TSH

levels above 10 mU/l. 2–4% of people with

subclinical hypothyroidism will progress to overt

hypothyroidism each year. The risk is higher in

those with antibodies against thyroid

peroxidase. Subclinical hypothyroidism is estimated

to affect approximately 2% of children; in the adults

subclinical hypothyroidism is more common in the

elderly, and in Caucasians. There is a much higher

rate of thyroid disorders, the most common of

which is hypothyroidism, in individuals with Down

syndrome and Turner syndrome [5].

Very severe hypothyroidism and myxedema coma is

rare, with it estimated to occur in 0.22 per million

people a year. The majority of cases occur in

women over 60 years of age, although it may

happen in all age groups [6]. Most hypothyroidism

is primary in nature. Central/secondary

hypothyroidism affects 1:20,000 to 1:80,000 of the

population, or about one out of every thousand

people with hypothyroidism [7].

METHODOLOGY (STEPS INVOLVED IN DRUG

DESIGNING)

BIOINFORMATICS

Literature Studies

In this research investigation we used Pubmed,

Pubmed Central and OMIM database in order to

obtain gene information on Hypothyroidism and

infertility related disorders. The gene ID’s for

Thyroglobulin (TG), Follicle Stimuating Hormone

Beta subunit (FSHB) and Synaptonemal Complex

Protein 3 (SYCP3) are 7038, 50511 and 2488

To whom correspondence should be addressed:

Anusha CS

Email: [email protected]

Abstract

Hypothyroidism is a common endocrine disorder in which the thyroid gland does not produce sufficient

thyroid hormone. It can cause a number of symptoms, such as tiredness, poor ability to tolerate cold, and

weight gain. In this insilico research, we identified protein target drugs have significant role in treating

hypothyroidism and associated female and male infertility disorders. The designed de novo drugs show

higher binding affinities when compared to the existing drugs. Hence by way of this project we discover de

novo drugs which act as potential therapeutic agents in controlling Hypothyroidism.

Keywords: Protein modeling, drug designing and docking.

RESEARCH ARTICLE

Anusha CS et al., Identification of in silico drugs and drug docking studies on hypothyroidism and inferility

disorders in human


respectively. Based on molecular genetics literature,

we identify the potential target for protein

modeling and drug designing studies.

Sequence Retrieval System

The genes sequences responsible for

Hypothyroidism and its associated disorders such as

infertility in male and female are retrieved from

human ensemble genome browser.

Protein modelling

The retrieved gene coded protein sequences are

applied into CPH 3.0 model server in order to

predict the 3 Dimensional structures of the protein

sequences.

Structure validation

The after converting the amino acids sequences

into 3D structures, the modelled structures are

validated through Rapper Server in order to identify

the structural quality based on the assessment of

Ramachandran plot values.

Protein Structure Visualization

The modelled protein 3D structures are viewed with

help of advanced molecular visualization software

called Discovery Studio in order to identify the

structural regions and to classify the entire 3D

structure elements.

CHEMINFORMATICS

Drug selection and identification

The potential chemical inhibitors are selected using

NCBI Pubchem chemical compound database

related to Hypothyroidism, male infertility and

female Infertility and then identified.

Drug designing and validation

We first select the existing drugs which are currently

used in medication for Hypothyroidism, male

infertility and female infertility. For the entire drug

designing and validation, we used a

Cheminformatics software called Mol inspiration.

Protein-drug docking

The modelled protein and designed de novo drugs

are docked using an automated molecular drug

docking server called Patch Dock server.

3d Protein-Drug Interaction Visualization

The protein –drug binding sites are viewed with

help of molecular visualization software like

Discovery Studio and Molegro Molecular Viewer

software.

RESULTS

Proteins rely upon the shape and properties of

functional areas of their three-dimensional structure

that is stable in normal environment to carry out

the biological functions. Knowledge of protein

structure is a key to understanding of the protein

function.

The protein sequences of the Thyroglobuin (Tg),

Follicle Stimulating Hormone Beta subunit (FSHB)

and Synaptonemal Complex Protein 3 (SYCP3)

protein targets for the study are retrieved from

NCBI and FASTA format in fig (1).

The three dimensional structure of Thyroglobulin

(Tg) protein is shown in fig (2). Ramachandran plot

value 87.5% of Thyroglobulin (Tg) protein is shown

in fig(3). The three dimensional structure of Follicle

Stimulating Hormone Beta subunit (FSHB) is shown

in fig (4). Ramachandran plot value 96.3% of

Follicle Stimulating Hormone Beta subunit (FSHB) is

shown in fig (5). The three dimensional structure of

Synaptonemal Complex Protein 3 (SYCP3) is shown

in fig (6). Ramachandran plot value 100% of

Synaptonemal Complex Protein 3 (SYCP3) is shown

in fig (7). Table 1. shows the selected existing drugs

of hypothyroid disorder and infertility. Fig (8) shows

the Ball and Stick model of Thyrotropin drug. Fig (9)

shows the Stick model of Cyclofenil drug. Fig (10)

shows the Space filled model of Methyltestosterone

drug. Table 2. shows the designed De Novo drugs

(Thyrotropin + Caffeine, Cyclofenil + Caffeine,

Methyltestosterone + Caffeine).

Table 3. shows the values of the molecular docking

(Docking of target proteins with existing drugs and

de novo drugs). Designing of Caffeine with existing

drug Thyrotropin (De novo drug 1) is shown in

fig(11).

Designing of Caffeine with existing drug Cyclofenil

(De novo drug 2) is shown in fig(12). Designing of

Caffeine with existing drug Methyltestosterone (De

novo drug 3) is shown in fig(13). Molecular docking

of Thyroglobulin (Tg) protein and existing drug

Thyrotropin is shown by Discovery Studio Software

in fig (14).

Molecular docking of Thyroglobulin (Tg) protein

and De novo drug 1 is shown by Discovery Studio

Software in fig (15). Molecular docking of Follicle

Stimulating Hormone Beta subunit (FSHB) protein

and existing drug Cyclofenil is shown by Molegro

Molecular viewer in fig (16). Molecular docking of


disorders in human


Follicle Stimulating Hormone Beta subunit (FSHB)

protein and De novo drug 2 is shown by Molegro

Molecular viewer in fig (17). Molecular docking of

Synaptonemal Complex Protein 3 (SYCP3) protein

and existing drug Methyltestosterone is shown by

Discovery Studio Software in fig (18). Molecular

docking of Synaptonemal Complex Protein 3

(SYCP3) protein and De novo drug 3 is shown by

Discovery Studio Software in fig (19).

Fig 1. FASTA Sequence protein sequence-

Thyroglobulin (TG)

MALVLEIFTLLASICWVSANIFEYQVDAQPLRPCELQRET

AFLKQADYVPQCAEDGSFQTVQCQNDGRSC

WCVGANGSEVLGSRQPGRPVACLSFCQLQKQQILLSG

YINSTDTSYLPQCQDSGDYAPVQCDVQQVQCWC

VDAEGMEVYGTRQLGRPKRCPRSCEIRNRRLLHGVGDK

SPPQCSAEGEFMPVQCKFVNTTDMMIFDLVHS

YNRFPDAFVTFSSFQRRFPEVSGYCHCADSQGRELAET

GLELLLDEIYDTIFAGLDLPSTFTETTLYRIL

QRRFLAVQSVISGRFRCPTKCEVERFTATSFGHPYVPSC

RRNGDYQAVQCQTEGPCWCVDAQGKEMHGTR

QQGEPPSCAEGQSCASERQQALSRLYFGTSGYFSQHDL

FSSPEKRWASPRVARFATSCPPTIKELFVDSG

LLRPMVEGQSQQFSVSENLLKEAIRAIFPSRGLARLALQF

TTNPKRLQQNLFGGKFLVNVGQFNLSGALG

TRGTFNFSQFFQQLGLASFLNGGRQEDLAKPLSVGLDS

NSSTGTPEAAKKDGTMNKPTVGSFGFEINLQE

NQNALKFLASLLELPEFLLFLQHAISVPEDVARDLGDVM

ETVLSSQTCEQTPERLFVPSCTTEGSYEDVQ

CFSGECWCVNSWGKELPGSRVRGGQPRCPTDCEKQR

ARMQSLMGSQPAGSTLFVPACTSEGHFLPVQCFN

SECYCVDAEGQAIPGTRSAIGKPKKCPTPCQLQSEQAFL

RTVQALLSNSSMLPTLSDTYIPQCSTDGQWR

QVQCNGPPEQVFELYQRWEAQNKGQDLTPAKLLVKIM

SYREAASGNFSLFIQSLYEAGQQDVFPVLSQYP

SLQDVPLAALEGKRPQPRENILLEPYLFWQILNGQLSQY

PGSYSDFSTPLAHFDLRNCWCVDEAGQELEG

MRSEPSKLPTCPGSCEEAKLRVLQFIRETEEIVSASNSSRF

PLGESFLVAKGIRLRNEDLGLPPLFPPRE

AFAEQFLRGSDYAIRLAAQSTLSFYQRRRFSPDDSAGAS

ALLRSGPYMPQCDAFGSWEPVQCHAGTGHCW

CVDEKGGFIPGSLTARSLQIPQCPTTCEKSRTSGLLSSWK

QARSQENPSPKDLFVPACLETGEYARLQAS

GAGTWCVDPASGEELRPGSSSSAQCPSLCNVLKSGVLS

RRVSPGYVPACRAEDGGFSPVQCDQAQGSCWC

VMDSGEEVPGTRVTGGQPACESPRCPLPFNASEVVGGT

ILCETISGPTGSAMQQCQLLCRQGSWSVFPPG

PLICSLESGRWESQLPQPRACQRPQLWQTIQTQGHFQL

QLPPGKMCSADYADLLQTFQVFILDELTARGF

CQIQVKTFGTLVSIPVCNNSSVQVGCLTRERLGVNVTW

KSRLEDIPVASLPDLHDIERALVGKDLLGRFT

DLIQSGSFQLHLDSKTFPAETIRFLQGDHFGTSPRTWFG

CSEGFYQVLTSEASQDGLGCVKCPEGSYSQD

EECIPCPVGFYQEQAGSLACVPCPVGRTTISAGAFSQTH

CVTDCQRNEAGLQCDQNGQYRASQKDRGSGK

AFCVDGEGRRLPWWETEAPLEDSQCLMMQKFEKVPES

KVIFDANAPVAVRSKVPDSEFPVMQCLTDCTED

EACSFFTVSTTEPEISCDFYAWTSDNVACMTSDQKRDA

LGNSKATSFGSLRCQVKVRSHGQDSPAVYLKK

GQGSTTTLQKRFEPTGFQNMLSGLYNPIVFSASGANLT

DAHLFCLLACDRDLCCDGFVLTQVQGGAIICG

LLSSPSVLLCNVKDWMDPSEAWANATCPGVTYDQESH

QVILRLGDQEFIKSLTPLEGTQDTFTNFQQVYL

WKDSDMGSRPESMGCRKDTVPRPASPTEAGLTTELFSP

VDLNQVIVNGNQSLSSQKHWLFKHLFSAQQAN

LWCLSRCVQEHSFCQLAEITESASLYFTCTLYPEAQVCD

DIMESNAQGCRLILPQMPKALFRKKVILEDK

VKNFYTRLPFQKLMGISIRNKVPMSEKSISNGFFECERRC

DADPCCTGFGFLNVSQLKGGEVTCLTLNSL

GIQMCSEENGGAWRILDCGSPDIEVHTYPFGWYQKPIA

QNNAPSFCPLVVLPSLTEKVSLDSWQSLALSS

VVVDPSIRHFDVAHVSTAATSNFSAVRDLCLSECSQHE

ACLITTLQTQPGAVRCMFYADTQSCTHSLQGQ

NCRLLLREEATHIYRKPGISLLSYEASVPSVPISTHGRLLG

RSQAIQVGTSWKQVDQFLGVPYAAPPLAE

RRFQAPEPLNWTGSWDASKPRASCWQPGTRTSTSPGV

SEDCLYLNVFIPQNVAPNASVLVFFHNTMDREE

SEGWPAIDGSFLAAVGNLIVVTASYRVGVFGFLSSGSGE

VSGNWGLLDQVAALTWVQTHIRGFGGDPRRV

SLAADRGGADVASIHLLTARATNSQLFRRAVLMGGSAL

SPAAVISHERAQQQAIALAKEVSCPMSSSQEV

VSCLRQKPANVLNDAQTKLLAVSGPFHYWGPVIDGHF

LREPPARALKRSLWVEVDLLIGSSQDDGLINRA

KAVKQFEESRGRTSSKTAFYQALQNSLGGEDSDARVEA

AATWYYSLEHSTDDYASFSRALENATRDYFII

CPIIDMASAWAKRARGNVFMYHAPENYGHGSLELLAD

VQFALGLPFYPAYEGQFSLEEKSLSLKIMQYFS

HFIRSGNPNYPYEFSRKVPTFATPWPDFVPRAGGENYKE

FSELLPNRQGLKKADCSFWSKYISSLKTSAD

GAKGGQSAESEEEELTAGSGLREDLLSLQEPGSKTYSK

Infertility Target Protein Male-Synaptonemal

Complex Protein 3 (SYCP3)

MVSSGKKYSRKSGKPSVEDQFTRAYDFETEDKKDLSGSE

EDVIEGKTAVIEKRRKKRSSAGVVEDMGGEV

QNMLEGVGVDINKALLAKRKRLEMYTKASLKTSNQKIE

HVWKTQQDQRQKLNQEYSQQFLTLFQQWDLDM

QKAEEQEEKILNMFRQQQKILQQSRIVQSQRLKTIKQLY

EQFIKSMEELEKNHDNLLTGAQNEFKKEMAM

LQKKIMMETQQQEIASVRKSLQSMLF

Infertility Target Protein Female- Follicle

Stimulating Hormone Beta subunit (FSHB)


disorders in human


>sp|P01225|FSHB_HUMAN Follitropin subunit beta

OS=Homo sapiens GN=FSHB PE=1 SV=2

MKTLQFFFLFCCWKAICCNSCELTNITIAIEKEECRFCISIN

TTWCAGYCYTRDLVYKDP

ARPKIQKTCTFKELVYETVRVPGCAHHADSLYTYPVATQ

CHCGKCDSDSTDCTVRGLGPS

YCSFGEMKE

Fig 2. 3D Structure of Thyroglobulin (TG) Protein

This picture indictes the α helix and β sheets and white indicating coil regions of thyroglobulin protein.

Fig 3. Structure Validation : Rapper-Pampage Server

Evaluation of residues

Number of residues in favoured region (~98.0% expected) : 449 ( 87.5%)

Number of residues in allowed region ( ~2.0% expected) : 46 ( 9.0%)

Number of residues in outlier region : 18 ( 3.5%)

The Thyroglobulin protein shows the Ramchandran plot value (87.5%). This value indicates the stability

of the protein structure.

Fig 4. 3D Structure of FSHB (Follicle stimulating hormone beta subunit) Protein

This picture indictes β sheets and white indicating coil regions of Follicle Stimulating Hormone Beta

subunit (FSHB) protein


disorders in human


Fig 5. Structure Validation Rapper-Rampage Serve


Residue [ 45 :TRP] (-139.22,-152.16) in Allowed region

Residue [ 63 :PRO] ( -73.08, 88.21) in Allowed region

Residue [ 64 :LYS] ( -90.85, 43.31) in Allowed region

Residue [ 84 :CYS] (-146.75,-162.81) in Allowed region

Number of residues in favoured region (~98.0% expected): 103 (96.3%)

Number of residues in allowed region (~2.0% expected): 4 (3.7%)

Number of residues in outlier region : 0 (0.0%)

The Follicle Stimulating Hormone Beta (FSHB) subunit protein shows the Ramchandran plot value

(96.3%). This value indicates the stability of the protein structure.

Fig 6. 3D Structure of Synaptonemal Complex Protein 3 (SYCP3)

This picture shows the three dimensional structure of Synaptonemal Complex Protein 3 indicating

oxygen, nitrogen, carbon and sulphur.

Fig 7. Structure Validation Rapper-Rampage Server


disorders in human



Number of residues in favoured region (~98.0% expected) : 150 (100.0%)

Number of residues in allowed region ( ~2.0% expected) : 0 ( 0.0%)

Number of residues in outlier region : 0 ( 0.0%)

The Synaptonemal Complex Protein 3 (SYCP3) shows the Ramachandran plot value (100%). This value

indicates the stability of the protein structure.

Table 1. Drug selection of hypothyroid disorder and infertility

Fig 8. 3D Struture of thyrotropin

This picture shows three dimensional structure of Thyrotropin drug indicating Oxygen, Nitrogen and

Carbon.

S.No Name Structure Smiles

1 Thyrotropin

C1CC(N(C1)C(=O)C(CC2=CN=CN2)NC(=O)C3CCC(

=O)N3)C(=O)N

2 Cyclofenil

CC(=O)OC1=CC=C(C=C1)C(=C2CCCCC2)C3=CC=C

(C=C3)OC(=O)C

3 Methyltestosterone

CC12CCC(=O)C=C1CCC3C2CCC4(C3CCC4(C)O)C


disorders in human


Fig 9. 3D Structure of cyclofenil Drug

This picture indicates three dimensional structure of Cyclofeni drug indicating oxygen and carbon.

Fig 10. 3D Structure of Methyltestosterone drug

This picture shows three dimensional structure of Methyltestosterone indicating oxygen and carbon.

Table 2. De Novo Drugs

Drugs SMILES

Thyrotropin+caffeine CN1C=NC2=C1C(=O)N(C(=O)N2C)CC1CC(N(C1)C(=O)C(CC2=CN=CN2)NC(=O

)C3CCC(=O)N3)C(=O)N

Cyclofenil +caffeine CN1C=NC2=C1C(=O)N(C(=O)N2C)CCC(=O)OC1=CC=C(C=C1)C(=C2CCCCC2)

C3=CC=C(C=C3)OC(=O)C

Methylthestosteron +

caffeine

CN1C=NC2=C1C(=O)N(C(=O)N2C)CCC12CCC(=O)C=C1CCC3C2CCC4(C3CCC4

(C)O)C

Table 3. MOLECULAR DRUG DOCKING

Thyroid target protein Existing drug De Novo drug

Thyroglobulin (TG) -229.50 -358.82

Table 3.1. Molecular Drug Docking

Female infertility target protein Existing drug De Novo drug

Follicle Stimulating Hormone Beta (FSHB) -367.21 -528.24

Table 3.2. Molecular Drug Docking

Male infertility target protein Existing drug De Novo drug

Synaptonemal Complex Protein 3 (SYCP3) -167.40 -266.75


disorders in human


Fig 11. 3D Structure of thyrotropin and caffeine drug

This picture shows three dimensional structure of De novo drug (Thyrotropin + Caffeine ).

Fig 12. 3D Structure of cyclofenil and caffeine drug

This picture shows the three dimensional structure of De novo drug (Cyclofenil +Caffeine).

Fig 13. 3D Structure of methyltesterone and caffeine drug

This picture shows the three dimensional structure of De novo drug (Methyltestosterone + Caffeine)


disorders in human


Fig 14. 3D Structure of thyroglobulin (TG) and Thyrotropin drug

This picture indicates the Protein-Drug complex indicating Protein in Secondary structure model and

drug in spacefill model in yellow green colour.

Fig 15. 3D Structure of thyroglobulin and thyrotropin and caffeine

This picture shows the Protein –drug complex indicating Ligand in Yellow green colour and Spacefill

model and Protein in Solid Ribbon Model.

Fig 16. 3D Structure of Follicle Stimulating hormone beta subunit (FSHB) and Cyclofenil drug

This picture shows three dimensional structure of Protein-Drug complex indicating Drug in green colour

Spacefilled model


disorders in human


Fig 17. 3D Structure of Follicle stimulating hormone (FSHB) protein (female infertility) and cyclofenil and

caffeine

This picture shows the Protein –drug complex indicating Ligand in green colour stick model

Fig 18. 3D Structure of synaptonemal complex protein 3(SYCP 3) protein (Male infertility) and

methyltesterone

This picture shows the Protein-drug complex indicating Protein in the Wire Frame model and Drug in the

Space fill model.

Fig 19. 3D Structure of synaptonemal complex protein 3(SYCP 3) protein (Male infertility) and

methyltesterone and caffeine (Denova drug)

This picture shows the Protein –drug complex indicating Ligand Yellow green color Spacefill model and

Protein in wire frame model.


disorders in human


DISCUSSION

A ligand is a substance that forms a complex with a

bio-molecule to serve a biological purpose. In a

narrower sense, it is a triggering molecule, binding

to a site on a target protein. The binding occurs by

intermolecular forces, such as ionic bonds, Vander

Waals forces.

The interaction of most binding ligands with their

binding sites can be characterized in terms of

binding affinity. In general, high affinity ligand

binding results from inter molecular forces between

the ligand at its receptor while low affinity ligand

binding involves less intermolecular force between

the ligand and its receptor. High affinity binding of

ligands to receptors is often physiologically

important when some of the binding energy can be

used to cause a conformational change in the

receptor, resulting in altered behavior of an

associated ion channel or enzyme.

Binding affinity data alone does not determine the

overall potency of a drug. Potency is a result of the

complex interplay of both the binding affinity and

ligand efficacy. Ligand efficacy refers to the ability

of the ligand to produce a biological response upon

binding to the target receptor and the quatitative

magnitude of the response.

Docking is the most commonly used in the field of

drug designing. Docking is frequently used to

predict the binding orientation of small molecule

drug to their target protein in order to predict the

affinity and activity of the small molecule. Hence

docking plays an important role in the rational

design of drugs. A binding interaction between a

small molecule ligand and an enzyme protein may

result in activation or inhibition of the enzyme or

hormone. If the protein is a receptor, ligand

binding may result in agonism or antagonism.

Hypothyroidism is a condition in which the thyroid

gland does not produce enough T4 hormone which

is more common in women than men.

Hypothyroidism can interfere with fertility in both

male and female.

Thyrotropin is a tripeptidal hormone produced by

the hypothalamus that stimulates the release of

Thyroid Stimulating Hormone (TSH). Thyrotropin

promotes the growth of the thyroid gland in the

neck and stimulates it to produce more thyroid

hormones. Thyrotropin is used clinically by

intravenous injection to diagnose the secondary

hypothyroidism. Thyrotropin also has anti-

depressant, anti-suicidal and anti-ageing properties.

Cyclofenil is a non-steroidal anti estrogen. It is

primarily used in the treatment of menstrual

disturbances and anovualtory infertility in women.

Methyltestosterone is a medication used in men

who do not make enough of a natural substance

called testosterone. In males, testosterone is

responsible for many normal functions, including

growth and development of the genitals, muscles,

and bones. It also helps to cause normal sexual

development in boys. Methyltestosterone is similar

to the natural testosterone produced by the body. It

belongs to a class of drugs known as androgens.

Methyltestosterone may also be used in certain

adolescent boys to cause puberty in those with

delayed puberty.

Serum thyroglobulin levels in healthy subjects and

in patients with thyroid disease was reported by

Torrigiani et al., (1968). Thyroglobulin was more

frequently detectable in the sera of thyroglobulin

concentrations were observed which correlated with

goiter size. Thyroglobulin levels were higher in the

patients giving a family history of thyroid disease. It

is known that increased thyroglobulin are released

by TSH stimulation of the thyroid in normal animals

and the higher levels seen in patients with active

Graves disease. Higher levels of thyroglobulin were

seen in untreated hyperthyroid patients and

permanent remission of thyroid gland was reported

in hyperthyroid patients with Carbimazole.

As per Ban et al., (2003), the 8q24 locus which

contains thyroglobulin gene was previously shown

to be strongly linked with auto immune thyroid

disase. The influence of Methimazole on

thyroglobulin-induced auto immune thyroiditis in

the rats was reported by Rennie et al., (1982).

Methimazole significantly impaired the induction

and reduced the severity of experimental auto

immune thyroid disease in rats.

Caffeine is a central nervous system and a

metabolic stimulant and is used both recreationally

and medically to reduce physical fatigue and

restore mental alertness when unusual weakness or

drowsiness occurs. Caffeine and other

methylxanthine derivatives are also used on

newborns to treat apnea and irregular heartbeats.

Caffeine stimulates the central nervous system first

at the higher levels, resulting in increased alertness

and wakefulness, faster and clearer flow of thought,

increased focus, and better general body

coordination.


disorders in human


Caffeine readily crosses the blood-brain barrier that

separates the blood stream from the interior of the

brain. Once in the brain, the principle mode of

action is a non selective antagonist of adenosine

receptors and is capable of binding the adenosine

receptors on the surface of cells without activating

them (an “antagonist” mechanism of action),

thereby acting as a competitive inhibitor.

Caffeine is a natural material obtained from plants

that acts as an energizer, mild doses can remove

lethargy, drowsiness and to certain extent acts as a

mood stabilizer.

The present investigation dealt with analyzing the

binding ability of the de novo drug containing

caffeine with hypothyroidism and infertility disorder

protein targets. Though mere binding or drug-

target interactions do not convey the effectiveness

of the drug for the disease, it is necessary to first

identify and analyze if such interactions exist and

thereby it would be easier to proceed with further

experimentation.

In molecular docking studies the existing

thyrotropin drug with thyroglobulin (TG) protein

showed binding value of (-229.50). The de novo

drug thyrotropin with caffeine binding with

thyroglobulin protein showed (-358.82).

The existing drug cyclofenil with follicle stimulating

hormone beta subunit (FSHB) protein showed the

binding value of (-367.21). The de novo drug

cyclofenil with caffeine interaction with follicle

stimulating hormone beta subunit protein showed

(-528.24).

The existing drug methyltestosterone with

synaptonemal complex protein 3 protein (SYCP3)

showed the binding value of (-167.40) and the

denovo drug methyltestosterone with caffeine

interaction with synaptonemal compex protein 3

showed (-266.75). The low negative energy values

indicate a stable system with better interaction

between targets and the drugs. Similar findings

have been reported in the calculation of

electrostatic salvation energies of protein structure.

The structure of the ligand binding to the target

receptor is one of the most important sources to

gain information about the basic mechanism of

interaction between the three-dimensional

structures of protein. Thus the results of docking

studies imitate protein-ligand interactions perfectly,

which may form the basis of further research in

drug development process. Moreover structural

knowledge of these specific target proteins with

their ligands will definitely improve drug potency

and selectivity.

The inhibition of the receptor is a successful

approach to influence the activity of the protein;

one can stop the metabolic cascade in which the

protein is involved. For such binding activity drugs

with very high binding affinity to the protein are

necessary and these drugs showed excellent

binding efficiency. The docking studies of these

targets (thyroglobuin, follicle stimulating hormone

beta subunit and synaptonemal complex protein 3)

give a better insight on the binding affinities of the

drugs which are known to control hypothyroidism

and infertility disorders.

These drugs in turn may be administered to control

and treat the disease more effectively. One of the

most promising developments evolved from the

study of human genes and proteins has been the

identification of potential new drugs for the

treatment of disease. It relies on genome and

proteome information to identify protein associated

with hypothyroidism and infertility which computer

software can then use it as target for new drug

development.

These drugs will fit to the active sites of the target

protein molecules and interfere with mode of action

of these proteins. This is the basis of drug-discovery

process, which aims to find new drugs to act upon

the target proteins. The process of drug docking

thus culminated in finding three potential new

drugs in activating the target proteins that are

involved in producing the disease. This in silico

studies revealed that the de novo drug has high

negative values thereby proving that it has high

binding affinities to both hypothyroid and infertility

protein targets.

CONCLUSION

The present research work was focused on

hypothyroidism associated with female and male

infertility disorders. The de novo drugs would

definitely be useful in curing patients affected by

hypothyroidism along with infertility disorders in

human beings. The identified protein target drugs

have significant role in treating hypothyroidism and

associated female and male infertility disorders. The

designed de novo drugs show higher binding

affinities when compared to the existing drugs. So

we strongly conclude that the de novo drugs are

potential therapeutic agents in controlling

Hypothyroidism.


disorders in human


REFERENCES

1. Cooper DS, Braverman LE ed. Werner &

Ingbar's the thyroid: a fundamental and clinical

text, 10th

ed., Philadelphia: Wolters

Kluwer/Lippincott Williams & Wilkins

Health., 2012, 552.

2. Garber JR, Cobin RH, Gharib H, Hennessey JV,

Klein I, Mechanick JI, Pessah-Pollack R, Singer

PA et al., Clinical Practice Guidelines for

Hypothyroidism in Adults. Thyroid, 2012,

22(12), 1200–1235.

3. Fatourechi, V. Subclinical Hypothyroidism: An

Update for Primary Care Physicians. Mayo

Clinic Proceedings, 2009, 84(1), 65–71.

4. Monzani A, Prodam F, Rapa A, Moia S, Agarla V,

Bellone S, Bona G. Endocrine disorders in

childhood and adolescence. Natural history of

subclinical hypothyroidism in children and

adolescents and potential effects of

replacement therapy: a review. European

Journal of Endocrinology, 2008, 168 (1).

5. Counts D, Varma, SK. Hypothyroidism in

children. Pediatrics in Review, 2009, 30(7), 251–

258.

6. Klubo-Gwiezdzinska J, Wartofsky L. Thyroid

emergencies. Medical Clinics of North

America, 2012, 96(2), 385–403.

7. Persani L. Clinical review: Central

hypothyroidism: pathogenic, diagnostic, and

therapeutic challenges. The Journal of Clinical

endocrinology and Metabolism (Review), 2012,

97(9), 3068–3078.

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