Hit identification

Many of these unwanted functionalities have been collected based on chemists feedback from hit identification and lead optimization projects, and by looking at compounds not considered good starting points for optimization by medicinal chemistry or difficult to synthesize [35]. However, one could say that beauty is in the eye of the beholder and selecting attractive chemical starting points depends upon the experience and prejudice of individual chemists. An interesting study at Pharmacia in which 13 chemists reviewed about 22000 compounds in a compound acquisition program showed that medicinal chemists were inconsistent in the compounds they reject [36]. Furthermore, it was found that individual medicinal chemists do not consistently reject the same compound. 

Figure 1 Examples of fragment hit identification (showing fragment and target, bioassay activity and screening method).

For the application of biomolecular NMR in the process of hit identification and hit validation, four important components have to be optimized (i) supply of the target molecule, (ii) selection of ligands, (iii) hardware for automated sample preparation and high-sensitivity measurements, and (iv) software tools for automated data evaluation. 

Certainly biomolecular NMR is not the single method which is important for hit identification in pharmaceutical research. It is always a combination of techniques and a team effort that leads to a successful drug. This can involve biologists (basic understanding, assay development, bio-informatics), chemists (both bench chemists and modelers), screening specialists (HTS/natural products) and spectroscopists (X-ray, optical methods, surface plasmon resonance, NMR). 

Compound purity (or integrity testing) is important to ensure purity in the early stages because erroneous activity or toxicity results may be obtained by impure compounds, ft is initiated during hit identification and continued into lead and candidate selection. 

The costs associated with hit identification using diverse assay systems and technologies as well as, alternatively, biophysical methods and approaches are regarded... 

In the past decade, MS has become an indispensable tool for the pharmaceutical industry at each stage in drug discovery (see Table 4.1 [4]). Primarily, MS has been employed at the drug development stage. However, due to major advances in affinity-based MS technologies, it is readily becoming a common tool for hit identification in the drug discovery process (see Table 4.2 [4]). A common theme... 

MS binding assays are also useful for library screening with subsequent hit identification. The concept is simple. First, a library is searched for active compounds in a competitive binding assay. If the result is positive (which is indicated by an increase of the marker signal), the target bound hit is liberated and identified. 

Biomolecular target Reversible chemistry Maximum fragment size (Da) Analytical method for hit identification... 

Balakin, . V, Kozintsev, A. V, Kiselyov, A. S., Savchuk, N. P. (2006) Rational design approaches to chemical libraries for hit identification. Curr Drug Discov Technol 3, 49-65. 

Pharmacophores for Hit Identification and Lead Profiling Applications and Validation... 

Pellecchia, M., Becattini, B., Crowell, K. J., et al. (2004) NMR-based techniques in the hit identification and optimisation processes. Expert Opin. Then Targets 8, 597-611. 

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