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Introduction High throughput screening technology has played a key role in the development of inhibitors against particular targets via in vitro assays. However every inhibitor cannot be used directly as a drug. It has to undergo a series of examinations and optimizations before use in living subjects. The inhibitors would have had a trifling significance if unable to be used in clinical trials. Hit and lead generation with subsequent optimization of leads enables the scientists to design the drugs which are fit for human use. Identification technologies Diverse array of technologies have been developed to cast designs of hits and leads of inhibitors e.g. parp inhibitors, apoptosis inhibitors etc. 1. HTS of DOS libraries DOS (diversity oriented synthesis) refers to the creation of large and diverse screening libraries by careful observation of chemistry of compounds. Instead of targeting a single biological targets, DOS libraries can screen thousands of targets in one go. Principle of generating DOS libraries involves creation of scaffolds that have appropriate size and binding affinity for certain biological targets. Some of these scaffolds have the ability to bind multiple targets. The benzodiazepine scaffold exemplifies one of such scaffold. The chance of getting positive hits which have high potential of turning into lead in HTS increases with the use of DOS libraries [1]. 2. Structures The biochemical knowledge of the ligand binding active site, against which the inhibitor is screened, proves to be highly useful in generating hits and leads. Certain leads have been developed using this technology, e.g. renin and HIV protease inhibitors, and matrix metalloprotease inhibitors. 3. Natural products Hit selection based on similarity with natural products is an excellent tool to achieve least negatives and maximum positive leads and candidates (optimized lead is called as candidate). Fingolimod is a drug whose design is based on natural product. 4. Peptides and peptidomimetics Compound libraries can be based on natural or synthetic peptides or peptidomimetics. Peptidomimetic is a small protein like chain which mimics peptide. Convenient and rapid synthesis of peptide analogs facilitates the use of this approach to identify successful hits and leads. Melanocortin receptors are involved in obesity and sexual dysfunction. Its active ligand in biological systems is ?-melanotrpin. Scientists designed a peptide base on the amino acid sequence of ?-melanotropin nad this minimally active sequce successfully inhibited the melanotropic receptors [2]. 5. Designs based on fragment screening Fragment screening is another approach to design hits and leads. Usually large number (<10000) fragments are often required to inhibit a target. After knowing about the particular atoms involved in inhibiting the targets, more specific inhibitors can be included in the inhibiting fragment [3]. 6. Designs based on Virtual HTS Computational modeling is highly significant in making virtual images of binding patterns of an inhibitor to its target. Inhibitor quality can be improved by making computational models of the inhibitors with targets. This is also called virtual screening. Virtual screening has also been used to develop better inhibitors against resistant drugs e.g. Dasatinib for Imatinib resistant patients. 7. Designs based on patents and literature It is also a wise strategy to study the inhibitors which are already available in literature or patents. They provide reliable models to inhibit their respective targets. E.g. several kinase inhibitors available in literature provide excellent references in optimizing hits and leads. Conclusion The process of drug discovery becomes more and more expensive as we move towards the final goal i.e. achievement of a clinically acceptable drug. Lead generation costs more than hit generation and clinical trials are even more expensive than the lead optimization step of drug discovery. By taking into account the above technologies, the rates of clinical failure of hits and leads can be minimized. If carefully designed inhibitors are used depending on the type of study being performed, chance of getting clinically positive hits and leads increases, which reduces the wastage of money on such random hits which will be of no use on application in clinical study. Not only this, precious time and effort of scientist or research group can be saved. Better results can be achieved in minimal time. Taken together, high throughput screening libraries are a blessing for drug discoverers. Careful and wise utility of this benediction can bring about cost effective drug discoveries! References 1.Chen, C. et al. (2005) Convergent diversity-oriented synthesis of small molecule hybrids. Angew. Chem., Int. Ed. 44, 2249–2252. 2.Newman, D.J. et al. (2003) Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod. 66, 1022–1037. 3.Zartler, E.R. and Shapiro, M.J. (2005) Fragonomics: fragment-based drug discovery. Curr. Opin. Chem. Biol. 9, 366–370. Related Posts Fingolimod is a Naturally Derived Prodrug The Process of HTS Related to Hit and Lead Generation Technologies HTS and Drug Discovery A man of Stone Age if brought into the contemporary world will not deem in the innovations made so far even after visualizing them. But ... The Process of HTS The urge to unveil the hidden truths of life, to reveal the concealed and to unleash the interred, has been native to human since birth. ... Advantages and Disadvantages of HTS Introduction: HTS can be pigeonholed as the first milestone in the excursion of drug discovery and biochemical research. Automation of fundamental processes including sample’s handling, ... 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