Lead evaluation

Determination of the IC50 is a preliminary evaluation of the relative affinity of different compounds for a target enzyme. To evaluate affinity properly, however, one must first define the mechanism of inhibition of the target enzyme by each compound. The next step in the lead evaluation flowchart (Figure 5.1) is to determine if the inhibition caused by a compound is rapidly reversible, slowly reversible, or irreversible. This information will help the investigator understand whether or not the inhibition reaction can be treated as a reversible equilibrium, and thus decide on the best measure of true affinity for a particular compound. 

Conceptual Advances in Lead Evaluation Screen Early and Often... 

Applied Biotechnology, Bristol Myers Squibb Co., Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA Lead Evaluation, Applied Biotechnology, Bristol Myers Squibb Co., Pharmaceutical Research Institute, Pennington, NJ 08534, USA... 

This chapter will briefly describe the supporting technologies and processes used in lead evaluation and lead profiling. In addition, the rationale behind particular assay designs used to construct selectivity panels for common target families will be discussed in detail. 

The aim of lead evaluation and profiling is to produce high quality, multiparameter data on every compound emanating from HTS or within a discovery program. The key components of this process are described in Figure 2, but basically include centralized capabilities for testing compounds in broad in vitro specificity panels and... 

Over the last decade, there has been a significant increase in laboratory automation and miniaturization, primarily driven by the needs of HTS laboratories. However, the real challenge for lead evaluation is somewhat different from HTS. In HTS, one bioassay tests many hundreds of thousands of compounds in a short span of time. In lead evaluation, smaller numbers of compounds - typically 10-100 - are put through an array of assays that remain relatively constant over a longer time... 

Having described some of the technologies and processes being used to support lead evaluation, a critical element for the overall effectiveness of such an operation is the range of bioassays used for profiling and selectivity testing. 

Figure 5 The lead evaluation robot above is loading a 384-well microtitre plate into a liquidhandling device. The robot move up and down a track, move plates between reagent addition stations, incubators and readers...

For this reason the appropriate molecular representation for diversity or similarity examination of a combinatorial library varies and depends on the purpose of library (e.g., general screening library, lead evaluation Hbrary, lead optimization library, etc.). 

Wang X, Kolasa T, El Kouhen OF et al (2007) Rapid hit to lead evaluation of pyrazolo[3, 4-d]pyrimidin-4-one as selective and orally bioavailable mGluRl antagonists. Bioorg Med Chem Lett 17 4303-4307... 

The final model returns the metabolic lability of novel compounds. With defined thresholds, the quantitative prediction is converted into a classification. This classification is used for flagging of compounds for experimental testing (e.g., in hit or lead evaluation). On the other hand, quantitative predictions are of value to guide compound optimization, if the applicability of the model has been demonstrated. This approach is illustrated in the following example of a multidimensional optimization program. 

Carol Ryan, Susan Scheei, Jacek Ostrowski, John Lupisella, Joyce Kuhns, Maureen Morgan, Kevin OMalley", Jonathan Lippy", Kenneth Locke", Litao Zhang, Michael Lawrence Michael Poss Michael Blanai, Ruth Wexler Todd Kirchgessnei, and Ellen Kick. (1) Discovery Chemistry, Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, (2) SATT-Synthesis, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, (3) Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, (4) Lead Evaluation, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543... 

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