Endothelin Antagonist - Essay Example

DRUG DISCOVERY By of the The of the The of the School The and The Date Introduction The drug discovery is initiated by the unmet clinical needs and clinical conditions lacking suitable treatments. The process of drug discovery is not a simple one. It is a complex process that may take up to a decade and half. The first step to the discovery is an idea that arises from conceptualization and serious brainstorming. This is followed by building a concrete hypothesis o release a new form of drug to the markets (Hughes et al, 2011). The process begins with approximately 10,000 compounds but ultimately ends up at only one drug reaching the markets. It is the process of with major contribution is drug metabolism and pharmacokinetics (Palmer, 2003). One of the fundamental processes discoveries of drugs is screening cascade, which relies on activity of the drug on a specific target with affinity to particular receptors. This is besides the potency of the drug side by side with the bioavailability of the drug when test it in vivo. Moreover, with drug metabolism if it takes orally or intravenously and its half-life, these are going parallel with reasonable dose for patient compliance (Claxton, Cramer, and Pierce, 2001). Endothelin Antagonist A vasoconstrictive peptide referred to as endothelin is physiologically secreted by the endothelial cells. The receptors are expressed as ETA and ETB and are present in a whole body or overproduced in a pathophysiology condition that effects many systems and influence blood pressure centrally and peripherally. This condition is treatable by the use of endothelin antagonist. With the use of the antagonist, the discovery of drugs increases the chances of survival of hypertensive patients. It also controls the condition of hypertension quite well (Kohan 2010). The intention of this workshop is to bring forward a design of a drug that antagonizes the endothelin effect. It will involve the screening of 500,000 compounds. The approximate budget for the whole process is a million dollars and the process is expected to take at least three months. Elimination method has been employed to discard the unwanted compounds in a step-by-step approach to ultimately end up with the most compatible compounds. The Discussion Result Binding assay Table 1: Test 1 results: Activity in ETA receptor binding assay % INHIBITION COMPOUND 100 LN-208 100 LN-015 90 LN-142 95 LN-292 60 LN-127 95 LN-216 90 LN-047 60 LN-209 A test has been conducted on the affinity to assist in the estimation of the antagonist activity of completing the binding sites of the receptors by displacement of the ligand. The concentration of the test was found to be 1*10-4 M. All other compounds were rejected since the percentage of inhibition was ≥ 10%. This percentage was considered very low and unsuitable for making ETA antagonist. Activity in high throughput screen Table 2:Test 2 results: Activity in high-throughput screens (A=active I=inactive) compound %inhibition PDE ECE CETP SH2 LN-208 100 A I I I LN-015 100 A A A A LN-142 90 I I I A LN-292 95 I I I I LN-127 60 I I I I LN-216 95 I I I I LN-047 90 I I A I LN-209 60 I I I I Three compounds have been eliminated in the screening for the activity of compound in high throughput screen. These three compounds are: LN-209, LN-216 and LN-015. In the first case, one the inhibition percentage stood at 60% which could not suffice as it was considered low. Therefore, so it is not highly potent. Moreover, its structure consists of sulfoxide group that is not preferable for use because of its metabolizing action. On the other hand, LN-216 had a high potency of 95%, and is mainly peptide. The biggest problem is faced with peptides is their low bioavailability if they orally taken unless modification of compounds are done. The problem is caused by presystemic enzymatic degradation and poor penetration of the intestinal membrane (Morishita andPeppas, 2006). The final one, LN-015 had the highest inhibition of 100%. However, it is also not preferred for use because its lack of selectivity. This implies that it binds to all receptors PDE, ECE, CETP and SH2 which could lead to the increase of its side effects. IC50 Table 3:Test 3 results:IC50 determination for ETA Receptor Binding Compound PIC50 LN-208 7 LN-142 8 LN-292 8 LN-127 Read More