Kodadek posits that combinatorial chemistry should be applied to large unbiased libraries for de novo screening efforts as was originally intended, in order to overcome the limitations of current compound collections. Basically he cites two ways to accomplish this; 1) diversity-oriented synthesis (DOS) which prepares libraries of compounds with varied structural motifs and 2) big, and I mean BIG, compound libraries with numbers described in scientific notation.
For those of you who don’t know what combinatorial chemistry is; it’s basically hedging your bets on drug discovery. It entails using synth-bots, automation, and algorithmic synth design to produce large libraries of potential “lead compounds”. Lead compounds are those bare bone drug prototype molecules that don’t necessarily work well, but do illicit something similar to the desired response at the target receptor. These leads are later derivatized into yet another large library of similar analogues that are “high-throughput screened” against cell lines, en vitro targets, and animals.
Typical combinatorial libraries contain anywhere from a few hundred to a few thousand compounds (usually produced in microgram quantities). Recent developments point to the fact that many of our compound libraries should in fact contain more like a few hundred thousand to a few million compounds. This helps alleviate something we call combinatorial bias, human creativity getting in the way of a truly algorithmic approach to drug discovery.
Finding a molecule to fit a receptor site can be thought of as trying to force a metric nut onto a standard bolt. Not an easy task. Combinatorial chemistry in essence tries to accomplish that by trying out several million different nuts all differing by 0.0001 mm.