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Enzyme-catalyzed platform opens magic: building a "green engine" for chemical reactions

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  • Time of issue:2020-01-17
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(Summary description)When the first rays of life awakened from the billions of years of evolution on Earth, enzyme-catalyzed reactions accompanied life.

Enzyme-catalyzed platform opens magic: building a "green engine" for chemical reactions

(Summary description)When the first rays of life awakened from the billions of years of evolution on Earth, enzyme-catalyzed reactions accompanied life.

  • Categories:Industry news
  • Author:
  • Origin:
  • Time of issue:2020-01-17
  • Views:10
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Shaoyao Mingkang / Report
When the first rays of life awakened from the billions of years of evolution on Earth, enzyme-catalyzed reactions accompanied life. Enzymes are widely present in various cells. Thousands of metabolic chemical reactions in the body are completed under the action of enzyme catalysis. It can be said that each living individual is like a wonderful chemical plant. Every time, every moment, an efficient and specific complex chemical reaction takes place, and enzymes are the biocatalysts that promote these magical reactions.
Chemists find inspiration from the mysterious organisms: Can the "enzymes" that exist in life and have magical effects be used in chemical synthesis? For more than a century, the mysterious and wonderful "enzyme" has become the object of research by many scientists from behind the scenes to the stage. Just last year, scholars of directed evolution of enzyme molecules also won the Nobel Prize in Chemistry.
 
 
▲ Structure model of enzyme-substrate transition state complex
 
Efforts to build an enzyme-catalyzed platform to carry "green engines" for chemical reactions
Lianhe Pharmaceutical Co., Ltd. has captured the huge potential of enzyme catalysis in chemical synthesis reactions more than ten years ago, and began to use enzymes in process development.
"Early customers would specify that a certain step of the reaction requires enzyme catalysis when they asked us. All we have to do is to scale up the enzyme catalysis in the laboratory into production," recalled Dr. Fu Xiaoyong, senior vice president of Hequan Pharmaceutical. We were thinking about the question, if the enzymes were not used in the process package given to us by our customers, would we still be able to provide solutions? Can we choose the enzyme that is most suitable for the project from the existing enzyme molecules in the market? "
Since 2013, Hequan Pharmaceutical has gradually established an enzyme-catalyzed R & D team, and in the production and development of more than 20 new drugs, it has realized the development of core processes for the preparation of key chiral intermediates based on enzymes, effectively reducing the generation of pollution sources, The purpose of sustainable development of green environmental protection. Since then, Hequan Pharmaceutical has become the first company in the CDMO industry to open the road to enzymatic catalysis, and has equipped the chemical reaction with an efficient and environmentally-friendly "green engine".
It is true that enzymes play an important role in chemical synthesis reactions as efficient and clean catalysts, but enzymes are still very delicate, and they are also very picky about the environment. Any change in temperature, pH, or environmental factors in the chemical solvent will change the catalytic ability of the enzyme. The catalytic ability will be reduced in some cases, and the catalytic ability will be completely lost in other cases. In addition, enzyme catalysis is specific: an enzyme can only catalyze one or one type of chemical reaction. Scientists have made an analogy-a key unlocks a lock.
So how to choose such a "characteristic" enzyme to meet the ever-changing chemical synthesis reaction? "Finding enzymes" has become an important step to promote the development of enzyme catalysis. But where to look for enzymes? What if I ca n’t find it?
 
AI technology combined with high-throughput screening to improve the efficiency of enzyme directed evolution
 
In fact, the types of enzymes available worldwide are very limited and cannot be compared with the scale of chemical reagents. Hequan Pharmaceuticals found that if we want to provide partners with efficient enzyme catalysis solutions, we must find specific enzymes that highly match the substrate and target product. In other words, in the future, if Hequan wants to go further in the field of enzyme catalysis, it must have the ability to "reform enzymes"! Therefore, Hequan Pharmaceutical's enzyme directed evolution platform emerged as the times require.
 
In 2018, Hequan Pharmaceutical's enzyme-directed evolution platform took a solid first step. In an important project, the synthesis of a key chiral intermediate requires a 5-step reaction and the yield is only 40%. However, as the project progresses to the late clinical stage (P2b / P3), there is an urgent need to improve efficiency and reduce costs. To this end, Hequan Pharmaceutical's enzyme catalysis team first screened the existing enzyme library and constructed a biocatalytic route, which replaced the original five-step reaction with only one step reaction, increasing the yield to 76% and reducing the cost by 1/3. However, this route still needs to use three enzymes, two coenzymes, and control the pH value of the solution. The operation is not easy, and the cost advantage is not obvious enough.
 
In order to solve this problem, the team used cutting-edge big data and artificial intelligence technology, and through innovative computer modeling, predicted a few structural regions that may have a significant effect on the catalytic activity of the enzyme. High-throughput directed evolution. The magic of computer modeling is that the structure of the enzyme can be predicted based on the amino acid sequence, and the enzyme molecule that matches the expected activity can be selected. Researchers need to transform the interaction of enzymes with substrates from chemical problems to computable mathematical problems. Then, a picking robot was used to quickly screen potential mutants recommended by the computer. In just one month, the team completed the enzyme evolution through two rounds of AI prediction and robot screening. The reaction can be completed with only one enzyme and one coenzyme, with a yield of 90% and a cost reduction of more than 70% compared to the earliest five-step chemical route. This work has been highly affirmed by partners, and at the same time has laid a high technical starting point for the next STA enzyme evolution business.
 
Today, Hequan Pharmaceuticals has a well-equipped high-throughput enzyme evolution laboratory, which integrates cutting-edge technologies such as structural biology, mathematical models, high-throughput screening, and computer drug design. The integrated enzyme directed evolution technology can realize the natural evolution process of millions of years in a few months, and the existing enzymes can be evolved in a targeted and selective way.
 
 
A picture to understand the high-throughput enzyme directed evolution technology of Hequan Pharmaceutical
 
If you compare the enzyme active center to a pocket, enzyme evolution is the process of pocket modification. When evolved with natural enzymes, non-natural substrates often do not match the pockets, resulting in low reaction conversion rates and poor selectivity. At this time, it is necessary to evolve the enzyme and modify the pocket.
First, we design various pockets that may fit the substrate through computational simulation. Then, these pockets were experimentally made, so-called mutants. Then, thousands of mutants were placed in a 96-well plate with a picking robot, and then substrates were added for high-throughput reaction, screening, and analysis. Then find mutants with high relative conversion and high selection. Through this round of screening, the matching degree between the substrate and the mutant pocket has been greatly improved compared to the natural enzyme, but it is not perfect. You need to use the optimized mutant to continue the next round of computer design, experiment, and screening ,analysis. After multiple rounds of optimization, the matching degree between substrate and pocket will reach a relatively good degree, and the enzyme evolution is completed, and a high conversion and high selectivity enzyme is obtained.
Screening enzyme, evolutionary enzyme, mass production enzyme
After years of development, Hequan Pharmaceutical's enzyme catalysis platform has also gone through the process of passive enzyme selection from the early stage to the active transformation and evolution of the enzyme. Synthetic enzymes are new enzymes, and if they cannot be produced, they cannot be used in process chemistry. Therefore, in the exploration of green chemistry, Hequan never stopped there, but continued to cultivate in the field of enzyme catalysis. Today, Hequan Pharmaceuticals has established an integrated capability platform for enzyme catalysis from screening to evolution to production in Shanghai Jinshan Base. Not only can we support our own needs for enzymes, but we can also provide customers with professional enzyme production services.
Dr. Fu Xiaoyong said: "Hequan not only has the ability to screen and evolve enzymes, but also has the ability to produce enzymes in batches. It can provide partners with a full range of enzyme catalysis services. In the future, we will vigorously develop our own enzyme-oriented evolution database Provide high-quality customized enzymatic services to more partners. "
At present, Hequan Pharmaceutical has more than thousands of batches of chemical reactions each year. It is expected that more and more reactions are expected to use enzyme catalysis technology in the future, which will greatly reduce the cost of large-scale production and improve efficiency. From screening enzymes, to evolutionary enzymes, to mass production enzymes, Hequan equips traditional chemical reactions with an efficient "green engine" and will lead green chemistry to a new future!
 

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