Identifying a high-performing KRED for API synthesis

The Challenge: The High Cost of Speed in Pharma

For both generics and pharmaceutical companies, speed to market is a critical driver of commercial success. While biocatalysis offers a superior path to synthesizing complex chiral APIs, the traditional enzyme discovery process —reliant on extensive, resource-intensive high-throughput screening (HTS)— creates a significant bottleneck. This time barrier often prevents the adoption of optimal enzymatic solutions.

Faced with this challenge, researchers from Boehringer Ingelheim, Christian-Albrechts University of Kiel, Gecco Biotech and Zymvol sought a faster, more efficient path to identify a specific ketoreductase (KRED) for a key pharmaceutical building block.

The Solution

Instead of embarking on an experimental campaign, the consortium partnered with Zymvol to leverage its BioMatchMaker® platform. The goal was to bypass discovery bottlenecks and deliver a small set of high-potential enzymes ready for immediate validation.

Zymvol’s in silico process involved:

1. Massive-Scale Screening: We computationally analyzed a sequence space of over 450,000 publicly available ketoreductases.
2. Intelligent Down-Selection: Using a multi-step filtering and molecular docking simulation process, BioMatchMaker® identified the key structural and energetic features required for the reaction.
3. Rapid Targeted Recommendation: In less than a month, we narrowed the pool down to just 16 top-tier candidates, precision-selected for their high probability of success, saving our partners months of lab work.

Results & Impact

• Predictive accuracy & de-risking
  Experimental testing of the 16 recommended enzymes confirmed that 8 were active hits. This 50% hit rate is a testament to the predictive power of BioMatchMaker®, de-risking the entire discovery phase and ensuring that valuable lab resources are focused exclusively on viable candidates.

• Ready for process development
  The top-performing enzyme, Tcalid SDR (Enzyme 15 – See research paper), delivered an outstanding combination of activity and precision. In a brief 30-minute reaction, it achieved a 63% conversion to the desired chiral alcohol and 100% enantiomeric excess (e.e.), meeting the stringent purity requirements for pharmaceutical ingredients. This result provides a potent, high-quality starting point for direct advancement into process optimization and scale-up.

Highlights

• 50% hit rate
  From 16 computationally-selected candidates, half were confirmed as active enzymes, drastically reducing lab validation costs and effort.
• 63% conversion
  Within a 30-min reaction, the enzyme showcased its effectiveness in turning the starting material into the desired product.
• 100% ee
  Within a 30-min reaction, the enzyme delivered perfect stereoselectivity by producing only the single, desired stereoisomer.

✱ This Success Story summarizes the results presented in a peer-reviewed research paper co-authored by scientists from Boehringer Ingelheim, Christian-Albrechts-University of Kiel, Gecco Biotech, and Zymvol.