Chemistry and biology:  a promising convergence in the “small drug discovery lab"

Drug discovery depends on the careful management of information produced by biologists and chemists. The interface between chemistry and biology is usually seen as a narrow communication band between scientists accustomed to sharing only a small proportion of their vocabulary. However, this interface is becoming with time a significant workspace as chemistry and biology tend to overlap and become indiscernible from each other. This growing overlap is a result of a very accurate molecular definition of many biological agents that control life, as well as a better and concrete structural definition of interactions between macromolecules themselves and between small compounds and macromolecules in the field of pharmacology.

Increasingly complex and diverse structures from cells and organisms are characterized at the molecular and atomic levels

When looking at Nobel Prizes in medicine or physiology, it appears that the rewarded accomplishments are more and more the results of combined molecular (chemical) and biological approaches to the study of biological pathways. Many of them enable drug discovery : RNAi, GPCRs, proteasome, discovery of the biological role of nitric oxide, structure of membrane-bound ion channels. The characterization at the atomic level of protein-protein interfaces, catalytic sites of enzymes, protein membrane interfaces has become common, thanks to an industrialization of protein crystallography X-ray diffraction, high field NMR, atomic force microscopy, two photon spectroscopy. We can obtain the same level of detail on biomolecules as is now available for small organic compounds. The number of publicly available 3-dimensional structures of macromolecules has grown exponentially from less than 800 in 1992 to 80,000 in 2012. More importantly, almost half of these have been obtained at a resolution between 1 to 2Å (in the range of a CC bond length) giving the medicinal chemist a basis for reliable molecular docking and drug design.

In the meantime, as extremely large and complex structures have become available, highly diverse media can now be reliably and rapidly analyzed thanks to the last generation of MS and associated databases. The diversity of small organic molecules produced by living organisms has already provided many important drugs (antibiotics, alkaloids and autacoids). These chemical ensembles can be re-explored much more systematically to understand human physiology (metabolome) and find active substances (parvome) which give new models and ideas to the medicinal chemist, opening new avenues in drug discovery and development.

Fast progress in organic synthesis blurs the boundaries between small organic compounds and biologics

During the last 15 years, many improvements in chemical synthesis such as new catalysts, microwave heating, generalization of solid phase synthesis, have significantly expanded the space of accessible compounds, both in complexity and molecular size. They also have dramatically accelerated the synthesis of biopolymers and their artificial derivatives (modified proteins, peptides and oligonucleotides, dendrimers).

Ultimately, the complete chemical synthesis of genes and genomes in small amounts is now possible without any nucleotide template, making gene synthesis a cheap commodity. Associated to high speed genome sequencing -another convergence of chemistry, physics and biology- chemical synthesis of genes has revolutionized protein production.

At the same time, drugs of increasing size and complexity such as fondaparinux, aptamers, and dsRNA can be obtained by chemical synthesis. Highly selective modifications (such as pegylation or lipidation) of peptides and proteins, synthesis of protein-albumin chimeras or dendrimers are also possible.

The border between biologics, traditionally characterized by their preparation process  and chemical compounds, characterized by a complete analysis of their structure, is not so relevant anymore. Indeed, many biomolecules can now be characterized by their structure using the most accurate analytical means currently available. In contrast, synthetic statistical copolymers, defined by the synthesis process, such as glatiramer for multiple sclerosis and sevelamer, have been approved by the FDA, making the distinction between bioproducts and chemicals less clear. To account for this, new guidelines regarding the definition of biologics and NMEs have been issued by the FDA.

Chemistry in living systems

Chemistry and biology can be even more intimately mixed. Biological objects are used by chemists as reactors (cells) or templates (proteins) to perform chemical synthesis. Bio-orthogonal chemical reactions referred to as “click chemistry” enable specific compound coupling in living cells, molecular tracking, cell imaging, and target identification.  There is a growing number of examples wherein medicinal chemists have used the protein target itself as a molecular template to catalyze the synthesis of high affinity ligands or inhibitors.

Small molecule Superheroes

The rapidly increasing disk capacity of computers and the availability of cheap laser diodes have brought confocal microscopy and image-based assays into the "high throughput labs". As a result, high content screening (HCS), whereby subtle morphological and biochemical changes on cells can be assessed automatically in 96 or 384-well plates, is now affordable by biotech and academic structures. Using  HCS and phenotypic screens, we can discover small molecules that have dramatic effects on cells,  traditionally achieved with biological agents (siRNA, peptides, proteins, antibodies...). For example liquinimod and fingolimod exert effects on immune cells that are comparable to LPS and monoclonal antibodies. Small molecules that bind specifically to bromodomains control the expression of specific genes. Another example of a therapeutic breakthrough is the launching of ivacaftor by Vertex, a small molecule modulator of the CFTR channel that is the first disease-modifying drug for cystic fibrosis. Also, small compounds are currently screened for cell reprogramming and stem cell differentiation, opening new avenues in regenerative medicine.

Breakthrough in analytics

More and more, we see powerful analytical instruments (LC-MS, LC-MSMS, HR MS), leaving the area of specialized platforms to enter chemistry and biology labs. These mass spectrometers are controlled with user-friendly software. Thus, cheap, rapid and straightforward interpretation of data by the end user (chemists or biologists), favors broader uses, the acceleration of research and dialogue between the disciplines. Imaging techniques based on mass spectrometry have also become more common and accelerate our understanding of compound fate in organisms.

Powerful desktop computers

While molecular modeling continues to require specific skills, protein visualization, idea generation through target visualization and enumeration of virtual libraries can now be realized on a desktop computer by the medicinal chemist himself. He can also perform complex sample analysis at his desktop, linked to spectrometers, computing and database servers. He learns by himself to observe biomolecules, to analyze data from complex experiments and interact in a productive way with computational chemists, analysts and biologists.

Consequences in drug discovery

Downsizing : the small drug discovery lab. While expensive clinical development will surely remain the prerogative of large multinational corporations, rational drug design, target selection, medicinal chemistry can be performed by smaller teams, enabling real drug discovery and selection in academic labs and small “biotech” companies. Rational drug design has become more efficient.

Creative thinking made easier : as biomolecules and chemical compounds are becoming more and more comparable and appear to everyone as belonging to the same world, it is likely that the creative process will be easier in the coming years. Bisociation, a concept introduced by Arthur Koestler in 1964 to designate mental occurrences simultaneously associated with two habitually incomparable contexts, is considered the essential mechanism of creative thinking.  We can be sure that creative thinking is now being facilitated in the community of chemists and biologists.

This may be reflected by the outstanding years 2010 and 2011 in terms of new drugs approved, including a large number of first-in-class drugs to treat severe diseases, such as vismodegib, a Hedgehog antagonist for advanced basocellular skin cancer, ivacaftor, a CFTR potentiator for cystic fibrosis, boceprevir and telaprevir, two inhibitors of the hepatitis C virus, to name a few which have been discovered by academics or small-size corporations.

Benoît Déprez
Université Lille2
Institut Pasteur de Lille