Markush structures—what they are, and how to draw them

Bringing Chemical Intelligence to Biopharmaceutical Research

by Jesse Harris, Marketing Communications Specialist

Webinar21-biologics
Biologics are a rapidly growing portion of the pharmaceutical marketplace. Total sales of biopharmaceuticals in 2020 were 270 billion USD, up from 149 billion USD in 2012. This rapid growth represents a business opportunity for pharmaceutical companies and a chance for new and improved treatments for patients.  

A critical requirement for biopharma to continue its growth is software that fits their needs. Biologics, like small molecule drugs, require professional analytical testing to ensure the quality of any therapeutics. Unfortunately, many software tools struggle to bridge the gap between biologics and biomolecules. Chemical intelligence helps scientists be more effective in their research, so they can bring higher quality biopharmaceuticals to market more quickly.

The Biologics Boom

The term “biopharmaceutical” is defined as a pharmaceutical produced by a biotechnological process using molecular biology methods (Brodacka, 2018). Also known as “biologics,” this broad class of therapeutics has been used to treat conditions such as cancer, autoimmune disorders, and diabetes.

The first biopharmaceutical to receive a patent was insulin; a short peptide used to treat diabetes. Since then, several types of biopharmaceuticals have been approved. Monoclonal antibodies are one of the most important by market share. The top two medications in 2020—Humira (AbbVie) and Keytruda (Merck)—were both monoclonal antibodies (mAb). Recombinant proteins, gene therapies, and antibody-drug conjugates (ADCs) have also achieved commercial approval. 

While biologics as a class have been around for almost 40 years, its rapid growth is recent. Between 1993 and 2013, only 84 new biologics license applications (BLAs) were granted by the FDA, an average of 4 per year. From 2014 to 2020, the FDA approved 82 BLAs, almost tripling the rate from the previous 20 years. This expansion has been fueled by several factors, including advances in molecular biology techniques, increased investment from pharmaceutical companies, and improved software tools to assist researchers.

Image001Approvals of Biologics License Applications by the FDA, 1993-2020 (Data from Mullard, 2021)

How Chemical Intelligence Powers Biopharmaceutical Research 

Software meant for biopharmaceutical research has evolved as the field has grown. Often, this software lacks the ability to manage analytical chemistry data. “Chemical intelligence” means an application that understands what chemicals are and how they interact. Chemicals are complex objects—they have a chemical formula, physical and chemical properties, can react with other compounds, and can be tested by a range of analytical methods. It is impossible to list all the possible facts about a chemical, so software must understand what a chemical entity is. 

To understand the importance of chemical intelligence, it is worth examining a popular application in biopharmaceutical research that is not chemically intelligent: Microsoft Excel®. While Excel is an excellent program for many uses, it is not designed for scientific research. You can paste chemical formulas or pictures of chemical structures into an Excel sheet, but the program does not understand them. You cannot search in Excel using a chemical structure. For analytical data, you can transcribe peak tables or add pictures of spectra into your spreadsheet, but the spreadsheet will not understand what they mean. This data is not digitalized, something many organizations are striving for; it’s simply chemistry on glass instead of paper. Excel can do many things, but it can’t think like a chemist.

Benefits of chemically intelligent software include:

  • Predict the chemical properties of chemical structures
  • Understand the relationship between reactants and products
  • Identify chemical structures and names in search queries
  • Connect analytical data from different sources to one compound

These benefits have a profound impact on the way chemical data is generated, managed, and shared.

Chemically Intelligent Biopharmaceutical Analytics

Chemically intelligent software is an essential tool for bridging the gap between small molecules and biopharmaceutical analysis. Small molecule drugs are typically a few dozen atoms in size, while biologics can be tens of thousands of atoms. Many of the analytical techniques used to test the structure and purity of small molecule pharmaceuticals need to be adapted for biopharmaceutical research.

Liquid chromatography is one technique that becomes more complicated when used for biologics. Chromatographers have long known that protein separation is not predictable in the same way as that of small molecules because of their size and propensity to change conformation.

To improve chromatographic predictions for proteins, researchers developed new techniques using ACD/Labs software. Methods include changing prediction equations to better match empirical protein behavior and adding chaotropic agents to reduce non-linear effects caused by conformational change. 

Learn more about in silico method development for the liquid chromatography separation of proteins and Method Selection Suite.

NMR also becomes more difficult for larger analytes. A biomolecule may have thousands of hydrogen atoms, requiring added levels of computer interpretation to solve. Resources such as the Biological Magnetic Resonance Data Bank (BMRB) are essential for interpreting NMR data from biomolecules. That’s why ACD/Labs has included the ability to read BMRB files in the Spectrus Platform. These files can be imported and used to assign peaks in NMR spectra of biomolecules, allowing researchers to apply the collected biomolecular NMR data and knowledge in these files to their analyses.

The Challenge of Biopharmaceutical Data Management

Generating analytical data is difficult enough, but scientists must also manage that information. It is not uncommon for researchers to have results scattered between multiple instruments across multiple laboratories. Aggregating and organizing that data into a form suitable for decision-making is often tedious and error prone. 

Data management during ADC development is an instructive example of this challenge. ADCs are a class of therapeutic where a mAb is connected to a pharmaceutically active molecule using a linker. ADCs work by pairing the targeting effect of the antibody with the pharmacological effect of the payload. This combination of features is especially effective in chemotherapy.

Each of the ADC’s components—the mAb, the payload, and the linker—are synthesized independently. Before assembling an ADC, scientists must verify the structure and purity of each component. Each component will need to be tested using several analytical techniques. Once the ADC is put together, it must again be analyzed to ensure the coupling is effective. This data is likely spread across many analytical instruments, which may be in distant locations. Bringing together this information in a workable format is a massive undertaking.

Luminata® simplifies your data management and assembly. This application brings together analytical results from across your project into one interface, allowing you to save time and effort. Luminata also enables you to search your data, create visualizations, and simplifies impurity tracking. To learn more about data management in the field of ADCs, and how Luminata enables ADC research, see our whitepaper on the subject, along with this accompanying interview.

The Future of Medicine

The rapid increase in biopharmaceutical approvals and sales indicates their tremendous opportunities in the coming years. Innovative software solutions play an essential role in unlocking that potential. To learn more about how ACD/Labs brings chemical intelligence to biopharmaceutical research, register for our webinar Boost Your Biologics Research with Chemically Intelligent Software.

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