Chimie combinatoire

Today, the discovery of new drugs is based on the demonstration, generally on a molecular scale, of the interaction of an organic molecule with a pharmacological target. This target is often a protein, more rarely a sugar or a nucleic acid involved in triggering the pathological state.

Advances in molecular biology and genetics have made it possible to identify numerous candidate targets, and to produce them in sufficient quantities for structural studies (NMR, X-rays). However, even with this information, molecular modeling and the ab initio design of organic molecules capable of interacting efficiently have never been successful. The failure of these rational techniques led researchers of new drugs (but also of pesticides, herbicides, etc.) to approach the problem empirically.

What's more, the ever-increasing development of pharmaceutical companies' screening capabilities and the growing number of potential targets have led to the synthesis capacities of traditional chemists being exceeded. Historical laboratory collections, which suffer from a lack of diversity and replenishment problems, have been exhausted by the massive recruitment of pharmacological screening campaigns. Natural products can still provide many original structures, but problems of origin (mainly the intertropical zone), structural determination and synthesis complexity are slowing down their development. Only a rationalization of synthesis methods could meet the growing demand for new molecules.

Over the past five years, combinatorial chemistry has emerged as a fundamental source of original molecules for drug discovery. As a result, it has been rapidly adopted by pharmaceutical companies, with the aim of developing systematic processes to reduce the time between characterizing a new target and bringing an active molecule to market.

The aim of this article is to take stock of the current state of this new "chemical philosophy", and to demonstrate what is at stake. After a general presentation of combinatorial chemistry and the various techniques developed in this field, we will take stock of the chemical reactions that are currently exploitable. The evolution of analytical methods will be presented, as well as the emergence of the concept of diversity and its evaluation by molecular modeling. Then we'll look at how combinatorial chemistry is being integrated into the drug discovery process, and at the companies where it has produced promising results. Finally, a few non-pharmaceutical applications will be presented.