DNA Encoded Library - The epoch-making revolution in drug discovery
Posted: Jan 25, 2019
The struggle between mankind and disease has been going on for thousands of years and will continue indefinitely. In this battlefield, pharmaceutical chemists are the mainstay of maintaining human health and fighting various diseases. However, the road to drug discovery is not smooth, and drug chemists face many difficult challenges that are hard to imagine. The development of new technologies and the ingenious application of various technologies can help drug chemists overcome difficulties more effectively and find more ideal drugs for fighting diseases.
DNA encoded library makes it possible for researchers to screen millions, billions, and even trillions of chemical compounds in a single, simple experiment, thanks to a DNA tag that encodes how each component in the library was made. Although the technology was invented 25 years ago, it’s only within the past five years that it’s become a mainstay of drug discovery. In this article we’ll deal with how the technology works as well as some recent success stories that pharmaceutical companies, biotechs, and academics have achieved using the technology.
How does DNA Encoded Library work?
The kinase activity of receptor interacting protein 1 (RIP1) plays an important role in tumor necrosis factor (TNF)-mediated inflammation. Therefore, inhibition of the activity of RIP1 is promising for the treatment of various inflammation-related diseases. Although some inhibitors have been reported, the effects and pharmacokinetic performance are not ideal. GSK scientist Harris et al first screened the compound library in the company's kinase project and identified a series of RIP1 inhibitors, but all have problems of large molecular weight, high lipophilicity, poor water solubility, and the risk of off-target. Later, with the expansion of compound library (2 million compounds), seed compound 8 was found, but rodent experiments found that oral effects are not good, the prospects are unknown as well.
To develop novel chemical structures, Harris et al. used their own DNA-encoded library of small molecule compounds. Through combinatorial chemistry strategies like ternary building blocks (BB1, BB2 and BB3, BB = Building Block) and sharing and merging (split-and-pool), a huge library of 7.7 billion capacity compounds was obtained. Among them, BB1 contributed little to the affinity, and the amide compound composed of BB2 and BB3 became a seed compound, and finally a series of benzoxazepinone compounds like RIP1 inhibitors were found, which have high activity and high selectivity, and good oral pharmacokinetics parameters.
Among them, the compound GSK'481 is only effective against RIP1 kinase in 456 kinases, showing excellent selectivity. Therefore, GSK '481 is expected to become a clinical drug candidate.
Although the drugs selected by the DNA-coding compound library technology have not yet been marketed, they have been questioned by many parties. According to published information, GSK2256294, a screening for a chronic obstructive pulmonary disease selected from a library of DNA-encoding compounds, has completed Phase I clinical trials, and two unpublished are alleged to have completed Phase II trials.
The emergence of this screening library technology solves the problem of simultaneously screening a large number of molecules with targets.
The library of DNA-encoding compounds differs from the library of common compounds in that each compound is linked to a specific DNA fragment at the molecular level to record information about the structure of the compound. At present, as a powerful tool for screening new drugs, DNA coding compound libraries have become more and more important for pharmaceutical companies and research institutes. A string of measures have been made to obtain the seed compound and greatly improve the efficiency of screening the new drug. At the same time, as the number of DNA-encoding compound library libraries increases, the range of target targets for trials is relatively difficult to cover from relatively simple targets to targets including protein-protein interactions, epigenetics, etc.
The status quo of DNA Encoded Library
DNA-encoding compound library technology has become a hot spot for the screening of new drugs. Although there are many research institutes and companies engaged in this technology, it is estimated that there are only three companies that can provide large-scale screening services for DNA-coding compound libraries in the world (X-chem, Nuevolution and Chengdu Pioneer. Since GSK does not provide screening services, so it is not counted). And the world has made great progress in the field of DNA coding compound library screening, and many inhibitors have been screened on the targets of many traditional screening techniques that are difficult to screen for small molecule compounds.
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