CM5044: LEAD COMPOUND IDENTIFICATION (2021-2022)

The use of in-silico techniques will be described to study the binding sites on host fragments in order to predict appropriate docking structures focussing on the shape and charge distribution of these molecules. It will be shown how these predictions may be used to identify appropriate commercial libraries of compounds. The principles used to screen these libraries will be described with emphasis on running high throughput screening assays. These lead to the identification of lead molecular scaffolds. The next stage involves systematic molecular structure changes and repeating the assays. It will be shown how these empirical Structure-Activity Relationships (SARs) are developed. This process is an iterative one, and identifies lead compounds. Methods to conduct structure alert analysis with a view to highlighting toxicity issues will be discussed. In parallel, the biological properties of these potential lead compounds need to be predicted and this will be described using industry-standard software (e.g. Stardrop). This predicts properties such as drug absorption, metabolism, and toxicity. The outcomes of all these studies are refined and normally a small group of candidate molecules are identified. Assays specific to target indication are performed and a small suite of molecules are taken forward for biological evaluation.

A second approach will also briefly be considered based on serendipity. A large number of new and untested molecules, often arising from natural sources, are screened and lead molecules discovered by good fortune. Examples of drugs discovered using this route will be discussed.

Information on contact teaching time is available from the course guide.

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