Assumptions Being Challenged
However, no one should get carried away by the idea that there are, post-genome, many thousands of new targets, according to Christopher Lipinski, Ph.D., senior research fellow at Pfizer (Groton, CT). This is just one of the many assumptions about drug discovery that needs to be challenged.
It is anybody's guess about the true number of drug targets, but it is probably in the low hundredsat least when it comes to looking at a single mechanism involving a single target for an oral drug. However, target opportunities do expand when nonoral drugs and polypharmacy are considered.
"Every clinically useful CNS drug is poly-pharmacological rather than selective," added Dr. Lipinski.
Low-dose oral drugs are also important, because no drug with a dose of less than 10 mg has ever been taken off the market. Unfortunately, in the present state of knowledge, finding such drugs is a matter of luck rather than logic.
"It is not really correct that drugs are becoming more potent. In fact, there has been little progress in getting low-dose drugs," noted Dr. Lipinski, who also pointed to the role of phenotypic screening, which was successful in the 1970s, before the advent of in vitro screening The move now to cell-based screening is welcome.
The combination of HTS and combichem has not been good for the industry and, as for genomics, it may have a positive impact on productivity a few years down the line, but it could also make things worse, according to Dr. Lipinski.
The rate of finding ligands that bind protein targets is lowthere have been only 24 new ligands over the last eight years and few of these have emerged from combichem.
What might help is to have academia, which is not forced to make money, work on targets that might be risky for commercial ventures.
Dr. Lipinski has been a pioneer in setting the ground rules of medicinal chemistry and does not think that the concept of "chemical diversity" is useful to the industry.
"The best way to never discover a hit is to rely on a chemically diverse library," he said.
After all, the targets that ligands bind are not chemically diverse; on the contrary there are a limited number of protein folds and only a few ways in which a protein molecule can form a site where a ligand can bind.
Of course, HTS does find some hits but this is not because of chemical diversity in libraries.
True diversity does not actually existexcept in silicofor various reasons. Only a finite number of compounds can actually be made because of the laws of chemistry and the availability of reagents.
And medicinal chemists are themselves biased, because of their individual experience. Library sizes are now going down (typically to below a hundred) and this has led to a better success rate in generating hits.