DNA-encoded chemical library (DECL) technology is used by the pharmaceutical industry to discover small molecules capable of modulating biologically relevant targets. DECL synthesis starts with an oligonucleotide that contains a chemical linker moiety, and proceeds through iterative cycles of DNA barcode elongation and chemical synthesis. DECL selections require little protein, minimal assay development and no specialized instrumentation. Parallel DECL selections can be easily conducted, making it possible to directly compare results across different conditions. The acquisition of building blocks is a large impediment when setting up a successful DECL platform. A potential solution is the sharing of building blocks between different labs, or the high-throughput parallel synthesis of novel building blocks. DNA-compatible reactions are required to join the building blocks together, and numerous academic labs have recently taken up this challenge. DECLs exist as unpurified mixtures, complicating data analysis. Machine learning may provide an improved ability to interrogate these data. DECL selections are largely limited to soluble purified proteins. However, progress has been made towards cell surface and in-cell selections. Publication guidelines are needed to better enable reproducibility; for example, the quantification of amplifiable DNA by quantitative PCR, and more complete datasets and building block lists, should be provided.
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- Public-knowledge-based rational design
Drug discovery starting with a publicly reported inhibitor, such as from the literature, patents or conference presentations.
- Combinatorial chemistry
A process that comprises mixing and splitting of intermediate products, leading to exponential growth of product numbers.
- Sticky end ligation of duplex DNA
Enzymatic joining of two duplex DNA fragments that contain short complementary single-stranded sequences, called overhangs.
- Splint ligation of single-stranded DNA
Enzymatic joining of two single-stranded DNA fragments with the help of a third DNA strand that is partially complementary to both fragments.
- Orthogonal functional groups
Functional groups that do not require protective groups when either of them is reacted in a synthesis route.
- Lipinski rule of five
A set of empirically found physicochemical compound properties that are statistically associated with oral bioavailability.
- Liquid chromatography–mass spectrometry
(LCMS). An instrument that allows for analysis of compound mixtures by separating them according to, for example, compound polarity and measuring product mass.
A synonym for chemical building block.
Powdered, soft, siliceous sedimentary rock.
- Phage-display technology
A technology that uses bacteriophages to connect peptides or proteins with the genetic information that encodes them.
- Medicinal chemistry optimization
The optimization of molecules towards properties suitable for application in animal tests and clinical tests.
The calculated logarithmic partition coefficient that indicates the portioning of a given molecule between water and octanol.
Description of molecular features that are required for recognition of a ligand by a biological target.
- Multiparameter optimization scoring
A method for deriving a score for the relative importance of selectable physicochemical properties, aiding in prioritization of molecules.
Area under the curve (from zero to infinity), which represents the total drug exposure across time.
- K d
Dissociation constant, the equilibrium constant of a non-covalent complex, for instance, formed by a drug-like molecule with its biological target molecule.
- Poisson distribution
A mathematical equation used to calculate the probability that a certain number of discrete events will occur.
- Confidence interval of 95%
Statistical estimate stating that there is a 95% chance that the unknown parameter will fall between the stated values.
- Click reactions
Robust, largely condition-insensitive reactions with a high thermodynamic driving force and a broad substrate scope.
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Satz, A.L., Brunschweiger, A., Flanagan, M.E. et al. DNA-encoded chemical libraries. Nat Rev Methods Primers 2, 3 (2022). https://doi.org/10.1038/s43586-021-00084-5