Learning from the generosity of nature: New libraries for drug discovery

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Learning from the generosity of nature: New libraries for drug discovery

Natural products, or their related derivatives, are some of our most powerful medicines, including macrocycles with their large carbon-rich cyclical systems as a class. The size and complexity of macrocycles have made it difficult to imitate and exploit nature's successes in the laboratory. By carrying out a complex molecular synthesis of these compounds attached to a single identifying DNA strand, the chemists at the University of Basel have built up a rich collection of natural product macrocycles that can be used for new drugs, as reported by researchers in the scientific journal Angewandte Chemie.

Natural evolution has created an incredible diversity of small molecular structures that disrupt living systems and are therefore used as drugs in medical applications. Although several dozen approved drugs are macrocyclic structures, almost all are natural products or related derivatives.

Finding new lead compounds in drug research requires huge banks of molecules with diverse structures, or simply rich collections of molecules. Medicinal chemists have failed to mimic nature's approach to bioactive macrocyclic molecules - and their long syntheses have prevented the creation of large screening libraries, which are essential for identifying potential drugs.

A challenge for synthetic chemistry

Researchers in the Department of Chemistry at the University of Basel have now completed the total synthesis of more than one million macrocycles that incorporate structural elements often observed in biologically active natural macrocycles.

The synthesis is based on the split-and-pool principle: Before a synthesis step, the entire library is divided. Then, each fraction is coupled to one of the different constituent elements and the newly constructed molecules are marked by a covalently attached DNA sequence. Before the next synthesis step, all fractions are grouped together again.

This leads to the cross-fertilization of all elements of diversity. Each combination is associated with a specific DNA bar code. Thanks to this approach, the 1.4 million members of the common library were examined in a single experiment. Sequencing the next generation DNA on the selected banks could then identify the macrocycles that bind to the target proteins.

Macrocycles are unlikely but powerful drugs

Most small molecule drugs are hydrophobic ("water-repellent") molecules of low molecular weight (less than 500 daltons). For this reason, these drugs tend to slide easily through cell membranes, exposing them to the vast majority of proteins important for the disease. Macrocycles go against this trend because they are often extremely large (more than 800 daltons) according to medicinal chemistry standards, yet they passively diffuse through cell membranes.

Researchers believe that this particular property of natural macrocycles stems from their ability to adapt their spatial structure (conformation) to the environment. Therefore, in the largely aqueous environment of blood circulation and cell interiors, macrocycles would expose their more hydrophilic groups to remain soluble. Once the hydrophobic cell membrane is encountered, a conformational displacement could allow the molecules to expose their hydrophobic side, making them soluble in the membranes and therefore capable of passive diffusion.

Possible new applications

Due to their unique properties, macrocycles are clearly under-represented in medicinal chemistry. This is largely due to the synthetic challenge of creating a large collection of macrocycles for screening. Using a bar-coded DNA strand, the Gillingham group overcame this obstacle by developing an effective seven-step synthesis of a macro-library of natural product-like macrocycles, all in a single solution.

"With a large and diverse collection of macrocycles available for screening, a more data-rich study on the properties of these extraordinary molecules can begin," says Dennis Gillingham. "This could reveal future medical applications, targets or active ingredients."