Written by:
Martin Hayes
Associate Principle Scientist, Discovery Sciences, AstraZeneca
Traditionally, many chemical reactions have not been performed in an environmentally friendly way, requiring the use of extreme temperatures, harsh organic solvents, and generating excessive waste. In recent years, biocatalysis has emerged as a more sustainable way to perform certain types of organic chemical reactions, many of which are crucial for drug discovery. Our new research shows that we can perform some common organic reactions – oxidation and amide bond synthesis – using biocatalysts, furthering our commitment to sustainable drug discovery and development.
What is biocatalysis?
Biocatalysis uses natural substances, called enzymes, to perform chemical reactions. Sometimes referred to as “nature’s catalysts”, these biocatalysts are fundamentally sustainable, and their use enables organic molecules to be produced in a milder manner compared to traditional chemical synthesis. For example, many biocatalysts provide a single step route to a desired molecule that may normally take up to five traditional organic synthesis steps. Consequently, there are several instances in which biocatalysis is not only more sustainable, it is also more efficient than traditional organic chemical synthesis.
How is biocatalysis important for our future of drug discovery?
To achieve our 2025 Zero Carbon Ambition and our 2030 Carbon Negative Ambition, it is essential that we approach R&D with sustainability at the forefront. Biocatalysis has a bright future of enabling us to perform important chemical reactions in a way that furthers this goal. Through advancements in the field of genomics, we are gaining access to a wider range of enzymes for catalysing chemical reactions. In addition, we can engineer enzymes that have the ability to perform non-natural chemistry. This means that over the next several years, the portfolio of chemical reactions that we can perform using biocatalysis will be much wider than it is now, opening the door for the possibility of many more sustainable chemical reactions in drug discovery.
What does our new research using biocatalysis show?
Our chemists recently published two high-impact publications on the use of biocatalysis in drug discovery: one involving an oxidation reaction and one involving amide bond synthesis.
Oxidation reactions using unspecific peroxygenase (UPO)
In collaboration with University of York, UK, we have utilised biocatalysts to build molecules that are otherwise difficult to synthesise. Unspecific peroxygenase (UPO) is a protein that facilitates the mild introduction of oxygen atoms to C-H bonds. However, UPO also requires hydrogen peroxide to function as a catalyst. We have shown that adding a second protein, called oxalate oxidase, produces optimal hydrogen peroxide levels for catalysis. The combination of the two biocatalysts in a ‘one pot’ reaction enabled an efficient and sustainable late-stage oxidation of a panel of drug molecules without the use of metal-based oxidants which are typically required for this type of reaction.
Amide bond synthesis
In collaboration with the University of Manchester, we have shown we can take a wide variety of carboxylic acids and amines and combine them to make amides using one enzyme for acid activation (carboxylic acid reductase) and one for amide bond formation (acyltransferase). This is one of the most widely used reactions in drug discovery and importantly, this biocatalytic step does not require the use of high temperatures or hazardous solvents. Even the catalysts themselves are sustainably produced and biodegradable.
Learn more about how biocatalysis is helping to make amide bond synthesis more sustainable in the animation below.
Sustainable reactions such as these are contributing to Green Chemistry practices within our R&D drug discovery programmes, enabling us to reach ambitious goals defined by our Ambition Zero Carbon Programme.
