Discovery phase, lead generation

As with turbidimetric assays, many of the direct UV absorbance assays are set up to determine kinetic solubility. However, the UV absorbance method also lends itself well to thermodynamic solubility determination by extending the period of sample agitation prior to filtration to 24 h or more. This offers a number of advantages. The solubility data generated are less dependent on the physical form of the initial material precipitated from DMSO and are much closer to thermodynamic solubility values determined later in discovery and in early development. As such, it gives more consistent solubility data through the discovery phase and enables a better quality early assessment to be made of the likely difficulties or otherwise of progressing a lead series into development. 

Mass spectrometry has been, and will continue to be, a critical tool for the discovery of new lead chemistries from nature. It continues to play a central role in several phases of the natural products discovery processes that include source selection, screening, dereplication, and identification. Mass spectrometry will likely remain a key technology that should contribute to the success of natural product lead generation programs in both the pharmaceutical and agrochemical industries. 

The aim of this section is to give an overview of the most common screening methods used in the hit generation phase. For a detailed description, the reader is directed to Lead Generation Approaches in Drug Discovery [5]. 

Lead generation is a key component of successful drug discovery. It is also the phase where the risks associated with drug discovery research are highest A number of collaborative approaches to lead generation have emerged in recent years. These are summarized in Table 11.1 and are reviewed in the following sections. 

In the discovery phase, MMV works with around 50 partners globally and its lead generation strategy has focused on phenotypic screening against the parasite Plasmodium falciparum. In collaboration with Novartis, GlaxoSmithKline (GSK), and St Jude Children s Research Hospital, over 5 million compounds were screened and the resultant 20 000 confirmed actives placed into the public... 

Lead generation offers an opportunity to initiate the drug discovery process with the best possible chemical starting points. In this phase, a project can survey a wide diversity of compoimds to identify novel compounds that balance potency with appropriate physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties and a low risk of toxicity. Later in the optimization process, when locked in to a small number of series, it may be much more difficult to improve one property without having a negative effect on another. 

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