Applying Chemetics® to Drug Discovery

Key Challenges and Limitations of Conventional Drug Discovery Approaches

Drug discovery companies are in constant need of new high-quality clinical candidates to feed their product development pipelines. However, despite huge increases in research spending, the drug discovery process still often fails to deliver lead molecules of appropriate quality to allow transformation of the leads into successful clinical candidates. The key limitations that can lead to failure include:

• At the world-leading facilities, “only” 1-5 million small molecules are currently screened using high-throughput screening. These small libraries (by Chemetics® standards!) can often lead to the generation of only a few ligands of low affinity, or no ligands at all.

• This very limited number of hits subsequently offers a poor starting point for lead generation, and as a result, very few leads are often generated, and those that are will typically be structurally similar.
  

• In many cases, most of the hits identified are not amenable to optimization through the use of combinatorial chemistry, but demand resource and time consuming medicinal chemistry efforts to optimize initial hits. In most cases, the hit diversification and hit-to-lead optimization will only allow the exploration of a few hundred to a few thousand of molecules, which further restricts the identification of a diverse set of leads.
  

• The small number and low diversity of hits and leads hampers the lead optimization process. As a result, preclinical candidates are chosen from rather non-diverse pools of sub-optimal leads. Thus, if a preclinical candidate fails, there are often few good, truly diverse back-ups in the series from which the lead candidate was chosen.
  

• Finally, the lead generation and lead optimization process typically adds to the molecular weight of the compound being optimized. This can often cause subsequent problems with bioavailability of such high molecular weight compounds.
  

Chemetics®-Driven Drug Discovery Solution

Chemetics®-driven drug discovery offers a number of significant advantages over the conventional drug discovery approach:

• The synthesis and screening of ultra-large, structurally-diverse libraries on an unprecedented scale - upwards of 100 million small molecules - facilitating efficient identification of hundreds of highly diverse hit and lead molecules rather than just a few.
  

• The large number and diversity of hits and leads generated offer an excellent starting point for lead optimization. Moreover, focused libraries of up to 100 million members may be generated, with all hits optimized in parallel, ultimately leading to a more diverse set of high quality optimized leads.
  

• Preclinical candidates may therefore be selected from the most diverse pool of optimized leads. In addition, if the lead candidate fails in preclinical studies, several good potential back-ups will be available with alternative structures.
  

• Through rapid generation of potent leads for a given target, it is possible to identify leads for several targets implicated in the same disease in parallel. The compound and target with the optimal therapeutic profile can then be selected for clinical development.
  

• Finally, the ability to generate large focused libraries also makes it possible to limit and tailor the size (and other properties) of the compounds as they are progressed through the optimization process, thus ensuring good bioavailability.