Discovery screening process

The third and very valuable discovery that the new phthalazine (PHAL) and pyrimidine (PYR) ligand classes (32-35, Figure 2) out-perform the monomeric ligands under identical conditions emerged from a heuristic screening process. The PHAL class in particular has become the first choice for most olefin classes. The PYR class is usually superior for terminal olefins, while the IND class is ideally suited for cA-disubstituted olefins. These ligands are commercially available or can be made easily from relatively inexpensive starting materials. 

One of the earliest approaches to drug discovery was the random screening process. More recently, significant efforts were directed towards... 

As a result of the screening process used during drug discovery, active substances will be identified. Of these active substances, the compound that best fits the desired characteristics profile (pharmacological activity, lack of early toxicity, patentability, etc) will be declared a lead compound. Development activities will then begin to shift from a broad discovery program to a more focused development program centred around the lead compound. 

One may think of an iterative model for the preclinical discovery screening cycle. A large number of compounds are to be mined for compounds that are active for example, that bind to a particular target. The compounds may come from different sources such as vendor catalogues, corporate collections, or combinatorial chemistry projects. In fact, the compounds need only to exist in a virtual sense, because in silico predictions in the form of a model can be made in a virtual screen (Section 8) which can then be used to decide which compounds should be physically made and tested. A mapping from the structure space of compounds to the descriptor space or property space provides covariates or explanatory variables that can be used to build predictive models. These models can help in the selection process, where a subset of available molecules is chosen for the biological screen. The experimental results of the biological screen (actives and inactives, or numeric potency values) are then used to learn more about the structure-activity relationship (SAR) which leads to new models and a new selection of compounds as the cycle renews. 

Fig. 3.1 Drug discovery sources in context. Different types of chemicai compounds (top left) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right).The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties.The candidate compounds then enter the development process involving regulatory toxicology studies and clinical trials.

---