tommysdad,
I pulled the following discussion of combinatorial chemistry from the PCOP website and am hoping that you or someone more conversant with the combichem field could discuss the merits of PCOP's "pool and synthesis" combinatorial approach compared with parallel or robotic synthesis. Which combichem companies are using the pool and synthesis besides PCOP and which are using parallel/robotic approaches? Here's the discussion:
Combinatorial chemistry is an approach to chemical synthesis that
enables the creation of large numbers of organic compounds by putting chemical building blocks together in every possible combination. It is used to synthesize compounds which are screened, or tested, against biological targets as part of the drug discovery process.
For most researchers, the drug discovery process has not changed significantly over the years. To discover a new drug, researchers first identify a disease target and then search for a chemical that will interact with that target. Most diseases are associated with changes in the amounts or activities of proteins within the body. Drugs are chemical compounds that improve health by interacting with proteins involved in diseases and modifying their activity.
Designing and synthesizing these chemical compounds which show activity against a target has always been a significant part of the drug discovery process. However, once a compound is found to be active against a relevant target, it rarely possesses all of the properties required to become a drug. Therefore, chemical analogs of the "active" compound must be synthesized and retested until a drug candidate with the desired characteristics is found.
Because it is extremely difficult to predict what chemical will react
with a target, and even more difficult to predict the optimal structure of that compound, many diverse compounds must be tested. However, a medicinal chemist using traditional synthesis methods can synthesize, on average, only one compound a week. As a result, synthesizing an adequate number of compounds to test against a target has historically taken years. Optimizing an active compound can require additional years, sometimes without success.
To address these challenges, two different methods of synthesis were developed in the mid-1980s. True combinatorial chemistry, as practiced by Pharmacopeia, is often referred to as "pool and split" synthesis. In this approach, chemists create compounds on tiny plastic beads which are divided among different containers. In each container, a different chemical building block is added. The beads in all containers are pooled and then split into a new set of containers. When the next building blocks are added to each container, they attach to all of the first building blocks at the same time, providing all possible combinations.
By performing only 50 individual reactions and using only 10 containers, Pharmacopeia's chemists can generate a large, diverse library of 100,000 small molecule compounds in a matter of weeks.
By contrast, many other practitioners are using a method called parallel, or robotic, synthesis. This practice simply involves performing a series of individual reactions in separate vessels. Similar to a chemist who performs a known reaction in a known vessel, this procedure can be made more efficient through the use of robots which can perform multiple reactions simultaneously.
To create the same 100,000 member library as in the pool and split synthesis example above, however, a chemist using parallel synthesis must complete 111,110 separate reactions and use 100,000 separate containers. Logistically, this is not feasible. As a result, the majority of libraries resulting from parallel synthesis contain only several thousand compounds.
While both combinatorial and parallel synthesis are widely used, combinatorial synthesis offers many advantages:
--Rapid Synthesis - libraries created using combinatorial synthesis require many fewer reaction steps than those created using parallel synthesis. As a result, time to synthesize a comparable size library is significantly less using the combinatorial approach.
--Large Numbers - Because combinatorial mixtures are pooled before each reaction step, thus providing every combination of the chemical building blocks involved, large libraries can be created using few steps and few reaction vessels. Parallel synthesis, by contrast, requires separate reactions in separate vessels, thus significantly limiting the number of compounds which can practically be made.
--Greater Structure-Activity Relationship (SAR) Data - SAR is the information linking a chemical structure with a biological activity. It is this data which guides medicinal chemists during the optimization process. Therefore, a library which results in a greater number of active "hits" provides the chemists with a better "roadmap" when designing analogs. Because combinatorial libraries are significantly larger than those created using the parallel approach, they typically result in more active hits and thus greater structure-activity relationship data.
--Increased Likelihood of Success - Libraries created using the parallel approach and those created using the combinatorial approach are both designed with medicinal chemistry knowledge to have desirable drug characteristics. However, it is difficult, if not impossible, to predict what chemical will react with a specific target, providing optimal results with a favorable side effect profile. Therefore, testing large numbers of medicinally-designed, diverse compounds increases the likelihood that active compounds will be discovered. Importantly, large numbers also increases the likelihood that potent, selective compounds will be discovered upon initial screening, thus minimizing the time, effort and expense of optimization.
--Broader Patent Protection - Another benefit of large combinatorial, identifiable libraries is the ability to document activity of a large number of compounds. This documentation is useful in seeking broad patent protection which could potentially block or slow competitors' attempts to develop competitive "me too" drugs.
Baird |
