New Compound For Specific Disease Biology Essay

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Screening process used to find new compound for specific disease.There are two scientific approaches to found new active compounds such as randomly collection from neutral sources throughout screening test and by ethnopharmacological selection process.For the screening of compound researcher used most relevant process called High-throughput Screening Which is very quicker method to conduct various test like pharmacologically activity, genetic test, bio-chemical test.. High-throughput screening (HTS) is very scientific and easy method to detection of drug discovery and development for therapeutically active molecular. Through HTS process, Biochemical pathway can be detected and gains initial view to start drug design of active molecular.

This process also used to run assay screening against many chemical compound to detect its stimulation or inhibition activity. If chosen target is G-protein couple receptor then drugs are tested for its inhibition and stimulation activity of antagonist and agonist receptor or if drugs are protein kinase then it tested for inhibition of belonging receptor. HTS also used for cross-screening to see chosen target hits with related compound. It is very precise because during hits toxicity produced between related target compound. Other method for screening is virtual high throughput screening, in which screening performed by computer based models to discover chosen target.

Workshop:-

When compound run throughout Cascade screening process, desirable properties like pharmacokinetic and pharmacodynemic are exhibits and interferior property rejected.

Objective:- ETA binding assays by cascade screening process.

Endothelin belongs to peptides family which show apeptidergic activity in endothelial cell by coronary vasoconstriction. There are three types of family such as Endothelin-1, Endothelin-2 and Endothelin-3 which act as cell proliferation, hormone production and vasomotor tone modulators. Endothelin bind to ETA and ETB receptor which is links together guanine nucleotide binding (GNB) protein. Affinity to bind Endothelin-1 to ETA is 10 times more than Endothelin-2 and 3.

Method:-

Following steps for ETA binding assay:-

Step:-1. Inhibition activity of active compound.

LN-208 and LN-015 shows 100% inhibition activity and LN-127 and LN-209 shows least activity so these compound removed.

All other compounds tested have inhibition < 10% so they all removed.

Table:-1. Below data show libery of compound and its inhibition activity in ETA receptor binding assay. (* Test concentration 1x10-4M)

COMPOUND*

% INHIBITION

LN-208

100%

LN-015

100%

LN-142

90%

LN-292

95%

LN-127

60%

LN-216

95%

LN-047

90%

LN-209

60%

Step:-2. Inhibition activity with related target check by HTS procees.

Following compound also shown activity with other target like PDE, ECE, CETP and SH2. So HTS process is very usful to indentified their activity.PDE is Phorbol Diester which is produce tumour in HL-60(human leukaemia) cell and regulated by TfR on cell surface. ECE is Endothelin converting enzyme which helps to convert bid Endothelin-1 to 21- amino acid- Endothelin-1. CETP is plasma lipid transfer protein which collects triglyceride from VLDL/LDL and transfer for cholesteryl ester. SH2 is protein domain which contain Src onco-protein and signalling protein.

LN-015 is show 100% inhibition but also active other compound like PDE,ECE, CETP and SH2 , so discarded due to produced interfear reaction.

LN-209 is not active other compound but its inhibition activity is too low 60%, so discarded.

LN-216 is show all inhibition activity with other compound and 95% but it is polypeptide structure and easily dissolved in small-intestile during oally administration and show amino acid structure like LN-292 during IV abministration, so it discarded.

Other compounds shown nice activity with %inhibitory so carry on for futher study.

Table:-2. Below data shows % inhibition of activity in High Throughput Screening.

Compound

% Inhib.

PDE

ECE

CETP

SH2

LN-208

100%

Active

Inactive

Inactive

Inactive

LN-015

100%

Active

Active

Active

Active

LN-142

90%

Inactive

Inactive

Inactive

Active

LN-292

95%

Inactive

Inactive

Inactive

Inactive

LN-127

60%

Inactive

Inactive

Inactive

Inactive

LN-216

95%

Inactive

Inactive

Inactive

Inactive

LN-047

90%

Inactive

Inactive

Active

Inactive

LN-209

60%

Inactive

Inactive

Inactive

Inactive

Step:-3. Determination of IC50 for ETA receptor binding.

IC50 (Half maximum inhibitory concentration) is required to measure concentration for antagonist and its potency to inhibit action toward receptor and minimizes action of bio-chemical reaction. Researcher measure negative value of IC50 (-log IC50) as pIC50 for potency of antagonist. Greater potency toward receptor shows higher value (above 7) to be consider.

LN-127 has less than 4 value mean higher affinity toward receptor so need more concentration of drug and formation of accumulation and toxicity, so it discarded.

LN-208 and LN-047 have 7 value or LN-142 and LN-292 have 8 value mean good potency to antagonist. So these compound can pass for next step for ETA receptor binding assay.

Table:-3. Below data show inhibitory concentration at plasma(pIC50) for various compounds.

Compound

pIC50

LN-208

7

LN-142

8

LN-292

8

LN-127

<4

LN-047

7

Step:-4. Determination of pA2 in rat Arota VS Endothelin.

Determination of pA2 is required to measurement of antagonist affinity toward receptor. pA2 mean dissociation constant of antagonist at equilibrium stage.

LN-208 and LN-047 has good affinity so it gain 7 value and also LN-292 and LN-142 have 8 value but in LN-142 also shown tissue contraction that mean it act as partial antagonist. So LN-142 is discarded due to produced toxicity.

Table:-4. Below data show pA2 value for diffarant compound.

Compound

pA2

LN-208

7

LN-142

8

Also contracts tissue

LN-292

8

LN-047

7

Step:-5.Measurment Intra venous activity of anaesthetised rat vs endithelin.

ID50 dose required for inhibit action toward endothelial mediated receptor for vasoconstriction of aorta. When dose administration by intravenously to Rat, it shown as:

LN-292 and LN-047 show 0.1 mg/kg and 0.5 mg/kg response respectively in infectious dose but LN-208 is inactive mean not reach to bind receptor and does not represent any activity in vivo but in vitro, it produced effect at different doses. So LN-208 is discarded for next test.

Table:-5. Below data show activity of Anaesthetised Rat vs Endithelin by I.V route.

Compound

ID50

LN-208

Inactive

LN-292

0.1 mg/kg

LN-047

0.5 mg/kg

Step:-6.Measurment oral activity of conscious rat vs endithelin.

Bioavailability is depending on first pass metabolism and intake of food or interaction of drug or present enzyme. When orally drug administration to conscious rat, it show as;

LN-047 has lower concentration (1 mg/kg) and LN-292 has higher concentration (100 mg/kg) means at the lower concentration LN-047 shows nice bioavailability with more effect but for LN-292 required highest dose. So it will discard

Table:-6. Below data show activity of Conscious Rat vs Endithelin by oral route.

Compound

ID50

LN-292

100 mg/kg

LN-047

1 mg/kg

Step:-7. Duration of action in conscious Rat .

When LN-047 compound administration orally to conscious rat, it show 50% activity in 30 minutes means drugs are very potent and adsoption is very fast. After 1 hr it shows 30% , 10% at 3hr and after 5 hr it not shown activity mean drug reach its maximum response of effect.

Duration of action is normal so it can be usefull for chronic disease.

Table:-7. Below data shown Duration of action in conscious Rat.( *% Inhibition with oral dose of 1 mg/kg)

Compound*

0.5 hr

1hr

3hr

5hr

LN-047

50%

30%

10%

0%

Conclusion:-

As per conclusion, cascade screening method is very useful for the detection of active compound . LS-047 is very potent compound and half-life is short so it can use in chronic attack. LS-047 requied lower dose to produce effect and show 90% inhibitory effect and also activate CEPT. So can also focus on new drug line discovery.

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