The pharmaceutical industry is now entering a crucial phase in its discovery of novel molecular targets where the role of the medicinal chemist is expected to further evolve and rise to this challenge of therapeutic innovation. The advent of systems biology and its contribution to a greater understanding of the molecular mechanisms and processes of intracellular cell regulation underpins the emerging and critical role of protein-protein interactions as potential therapeutic targets.

Consequently, it is fundamental to integrate as early as possible structural biology approaches in order to permit medicinal chemists to ‘construct’ their molecular scaffolds using fragment-based approaches. It is no longer a 2-dimensional perspective that will define or guide a chemical strategy, but more specifically, the complex spatial description of molecules as well as the integration of multiple parameters such as charge and polarity which will need to be evaluated through each step of the process. The advent of biophysics and the possibility of measuring molecular interactions between protein partners (NMR, MS, X-ray, CD, ITC, DSC, Biacore…) has become an additional but critical ally of the modern medicinal chemist.

The molecular challenges constituted by these ‘newly identified’ protein-protein interaction targets also require us to consider additional target-based approaches (pseudopeptides, polymers, oligonucleotides…) where access to a greater arsenal of molecular diversity is the key to success in therapeutic innovation. The capacity to ‘model’ molecular space is now a pivotal instrument in the selection of promising chemical scaffolds. The optimisation of a chemical lead into a drug candidate also requires the early integration of biopharmaceutical parameters (solubility, permeability, binding to transport proteins and metabolism) where the predictive potential of in vitro model systems is in constant progression.

These are some of the themes that will be addressed, and ardently discussed, at the forthcoming 47th edition of the ‘Therapeutic Chemistry’ meeting in Lyon in July 2011.

Dr Bernard Marchand
Head of Discovery Research
Servier Research Institute