Combinatorial Chemistry and HTS, Proteins, Pleiotropic Effect, Mitosis, Phosphonucleolin Staining

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Combinatorial chemistry and HTS

In the recent past, combinatorial libraries with high degree of diversity have been prepared for drug discovery (for combinatorial libraries see next section. All compounds in such a library are then screened against a panel of functionally dissimilar proteins, so that the binding affinity of each compound in the library for each target protein may be determined. The set of binding affinities of a compound (future drug) for different target proteins is described as its affinity fingerprint. It has been shown that similarity in fingerprints of compounds correlate with the biological activities of these drug like substances, suggesting that affinity fingerprints can be effectively used for drug discovery.

The three dimensional structures of proteins also help in drug discovery, since it helps in the study of protein-protein interactions that are relevant to drug discovery. For instance, the binding of immunoglobulin E (IgE), vascular endothelial growth factor (EGF), or interleukins (IL-2 or IL-5) to their corresponding receptors represent very attractive drug targets for treatment of allergies, cancer, autoimmune diseases, or asthma. This is particularly important, when small-molecule drug discovery fails with some targets. The study of protein protein interactions resolve small regions that are critical to binding and are therefore described as hot spots. Some small molecules target these hot spots and disrupt undesirable protein-protein interactions, thus becoming strong candidates for drug discovery.

Whole cell mitotic arrest assay	In vitro Tubulin polymerization assay (molecules targeting were rejected)	In vitro staining for chromosomes and Tubulin
(a) high throughput screening on the basis of the effects of compounds on microtubules, actin and chromatic
139 out of 16,320 compounds (based on increase in phosponculeolin staining)	86 no effects	5 affect only mitosis
	52 destablize	42 affect Interphase and mitosis
	1 stabilizes	27 no visible effect
		12 pleiotropic effects
(b) summary of screening results

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