Learning from nature's bounty: New libraries for drug discovery
Natural products or their approximate derivatives make some of our most effective drugs, of which macrocyclic compounds with large carbon-rich ring systems are one class. The size and complexity of the large ring makes it difficult to imitate and build natural success in the laboratory. Researchers report in the journal Science that by completing the complex molecular synthesis of these compounds, these compounds are linked to a uniquely identified DNA strand, and chemists at the University of Basel have developed a rich natural product, a macrocyclic compound, that can be used to extract new drugs. Angewandte Chemie.
Natural evolution has created an incredible array of small molecular structures that disrupt the life system and are therefore used as medicines in medical applications. Although dozens of approved drugs are macrocyclic structures, almost all of these are natural products or intimate derivatives.
In order to find new lead compounds in drug research, large libraries with multiple structures are needed - or simply put, a rich collection of molecules. Medicinal chemists have failed to mimic Nature's research on biologically active macrocyclic molecules - and their long-term synthesis has failed to create large screening libraries, which is critical for identifying drugs.
Synthetic chemistry challenge
Researchers at the University of Basel's Department of Chemistry have now completed the total synthesis of more than one million macrocyclic compounds containing structural elements commonly observed in natural bioactive macrocyclic compounds.
The synthesis is based on the split and pool principle: the entire library is split before the synthesis step. Each fraction is then coupled to one of the various building blocks and the newly constructed molecule is labeled with a covalently linked DNA sequence. All fractions are merged again before the next synthesis step.
This leads to a cross-combination of all diversity elements. Each combination is attached to a specific DNA barcode. In this way, all 1.4 million members of the pooled library can be screened in one experiment. The next generation DNA sequencing of the selected library can then identify the macrocyclic compound that binds to the target protein.
Macrocycline is unlikely to be a potent drug
Most small molecule drugs are hydrophobic molecules ("water repellents") with low molecular weight (less than 500 Daltons). Therefore, these drugs tend to slide through the cell membrane without problems, exposing them to most disease-related proteins. Macrocycles reverse this trend because they are usually very large by medicinal chemistry standards (more than 800 Daltons), but they passively diffuse through the cell membrane.
The researchers speculate that this particular property of natural macrocycles stems from their ability to adjust their spatial structure (conformation) according to the medium. Thus, in a substantially water-based environment within the bloodstream and inside the cell, the macrocyclic compound will expose its more water compatible (hydrophilic) groups to remain soluble. Upon encountering a hydrophobic cell membrane, a conformational transition exposes the molecule to its hydrophobic surface, making it soluble in the membrane and thus capable of passive diffusion.
New application possible
Due to its unique nature, macrocyclic compounds are clearly deficient in medicinal chemistry. This is mainly due to the combined challenge of creating large quantities of macrocyclic compounds for screening. With the help of the barcode DNA strand, the Gillingham team overcame this obstacle by developing an effective seven-step synthesis that aggregates a large ring library of natural products in one solution.
Dennis Gillingham commented: "With a large number of different macrocyclic compounds available for screening, more data can be studied for the properties of these extraordinary molecules."
