Lead Validation

With no shortage of drug targets, increasing emphasis is being placed on lead validation. One key challenge is developing high throughput screens. High-throughput screening (HTS) aims to rapidly assess the therapeutic value of a large number of compounds on a given target from a combinatorial library or other compound collection, often by running parallel assays. Today, High Throughput Screening represents the predominant tool for identifying leads for further drug development.

Primary HTS screens identify hits. Subsequently confirmation screens will then identify lead compounds out of the pool of hits. The success of screening depends on the availability of compounds, as well as their quality and diversity. Confirmed hits proceed to a series of counterscreens, which usually include drug targets of the same protein or receptor family. Counterscreens profile the action of a confirmed hit on a defined spectrum of biological target classes

One of the goals throughout the discovery of novel drugs is to establish and confirm the mechanism of action (MOA). In an ideal scenario, the MOA remains consistent from the level of molecular screening of a novel drug compound through the physiological response in an animal disease model, and ultimately in the patient.

The reliability of an animal model to predict the outcome in human clinical trails varies widely between diseases and has to be assessed on a case-by-case basis. In vivo models involve the whole organism of an animal. In complex organism both pharmacology and biological efficacy can be tested in parallel. Experts, both from industry and regulatory agencies, believe that this experimental gap represents one of the major hurdles in drug discovery and development. By the use of genetically modified mice, both knockout and transgenic mice, the field has made enormous progress in the last decade to specific mimic human diseases. As a consequence the predictive power of mice models for human disease and pharmacology is improving. With emerging knowledge of whole genomes, the value of animal models for drug development is increasing, especially if these animal models are not only used to study specific diseases, but also the underlying pathways, which give answers from pharmacology to understanding of the mode of action.

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