Combining intelligent design and combinatorial synthesis of libraries can provide a much more efficient route to drug discovery and lead optimization, according to Zhengming Chen, Ph.D., director of chemistry at Dov Pharmaceuticals(www.dovpharm.com).
"The best practice in library synthesis today is determining which compounds should be synthesized rather than settling for what can be made," Dr. Chen suggested. "At the core of this trend toward high-quality smart libraries is the link between library design and the specific biological target."
The drive for intelligent design involves surveying all available knowledge about a target, such as reviewing genomic and proteomics databases about the specific biological target protein, known patents on the target, known ligands for the target, and scientific publications related to the target and ligands.
"It is better and wiser to use intelligent design at lead-generation and lead-optimization stages. Our studies taught us several lessons. First, data and numbers alone are not sufficient for efficiently discovering new drugs. There is a huge amount of information being generated from genomics, proteomics, high-throughput screening, and rapid combinatorial chemistry.
"Second, intelligent design is emerging as a leading technique. The library size per scaffold peaked 5-6 years ago and has steadily declined since then. Now, instead of libraries containing several hundred compounds, we see libraries consisting of 20-100 compounds. These can be made more quickly and it provides us with shorter cycle times in drug discovery process.
"Third, the balance in drug discovery today is shifting from the concept of industrializing the drug discovery process into intellectualizing it. High-throughput synthesis and traditional medicinal chemistry are joining forces to create libraries that are both smaller and smarter in order to generate high quality in vitro and in vivo data. This is the future of drug discovery."