Yagong Wang ,  Hangke Ma ,  Ivan Hu ,  Jin Liang ,  Bingxin Chen ,  Lijun Xue ,  Kexin Yang ,  Yun Jin Hu

Organic Letters 

DOI: 10.1021/acs.orglett.5c04043

Abstract

We present a metal-free photochemical strategy for the synthesis of on-DNA β-hydroxy sulfides, which are essential pharmacophores with limited access via existing DNA-encoded library (DEL) methodologies. This innovative hydrothiolation features a broad substrate scope with both thiols and olefins. Its operational simplicity and excellent DNA compatibility enable the efficient construction of diverse DELs, significantly expanding the accessible chemical space for drug discovery and providing a new tool for identifying novel therapeutics.

Summary

This study introduces a novel metal-free, photoinduced method for synthesizing β-hydroxy sulfides on DNA. The approach leverages visible light to drive the reaction, avoiding the use of metal catalysts that can be harmful to DNA. The protocol is characterized by its operational simplicity, broad substrate scope, and excellent compatibility with DNA, making it highly suitable for constructing diverse DNA-encoded libraries (DELs). This method significantly expands the chemical space accessible for drug discovery and offers a powerful tool for identifying new therapeutic agents.

Highlights

• Metal-Free and Photoinduced: The method is metal-free and utilizes visible light, avoiding conditions harmful to DNA.
• Broad Substrate Scope: The reaction tolerates a wide range of thiols and olefins, including both aromatic and aliphatic substrates.
• Operational Simplicity: The protocol is straightforward, requiring only readily available starting materials and mild reaction conditions.
• DNA Compatibility: The method is highly compatible with DNA, enabling efficient construction of DELs without significant DNA damage.
• Expands Chemical Space: This approach significantly broadens the chemical space accessible for DEL-based drug discovery.

Conclusion

The development of a metal-free, photochemical β-hydrothiolation for the on-DNA synthesis of β-hydroxy sulfides represents a significant advancement in the field of DNA-encoded library synthesis. This operationally simple protocol demonstrates excellent functional group tolerance and DNA compatibility, enabling the efficient construction of a diverse DNA-encoded library from readily available thiols and disulfides. The method provides a powerful and versatile tool that significantly expands the accessible chemical space for DEL-based drug discovery, offering a new avenue for identifying novel therapeutic agents.

Wei Zhou, Yan Wang, Shuning Zhang, Chengwei Zhang, Jiacheng Pang, Shaoneng Hou, Jie Li, Ying Yao, An Su, Peixiang Ma, Hongtao Xu, Wei Hou

Chemical Science 

DOI: 10.1039/d5sc05512a

Abstract

Chemical reactions compatible with multiple functionalities are essential for rapid, programmable, and automatable synthesis of functional molecules. However, achieving such reactivity poses significant challenges. Here, we developed a novel multi-orthogonal C(sp 2 )-Se bond formation reaction between benzoselenazolones and boronic acids via Ag(I)catalyzed selective selenium(II)-nitrogen exchange. This chemistry is compatible with diverse functionalities, enabling sequential and programmable synthesis. Moreover, it features modular, high-yielding (485 examples, with yields or conversions exceeding 70% in 95% cases), and switchable reaction systems under mild conditions. Its practical utility was exemplified through late-stage functionalization of natural products, peptides modification and ligation, diversified synthesis, sequential click chemistry, protecting group-free syntheses of sequence-defined oligoselenide (nonamer), on-plate nanomole-scale parallel synthesis (200 nmol, 412 selenides), and DNA-encoded library (DEL) synthesis (10 nmol, 92 examples). Notably, a target-based screening identified SA-16 as a potent CAXII inhibitor with an IC 50 value of 72 nM. Furthermore, a machine learning-based model (SeNEx-ML) was established for reaction yield prediction, achieving 80% accuracy in binary classification and 70% balanced accuracy in ternary classification. These results demonstrated that this chemistry serves as a powerful tool to bridge the selenium chemical space with the existing chemical world, offering transformative potential across multidisciplinary fields.

Summary

This article presents a novel, highly selective, and AI-predictable selenium(II)-nitrogen exchange (SeNEx) chemistry between benzoselenazolones and boronic acids. The Ag(I)-catalyzed reaction forms C(sp²)-Se bonds and is compatible with a wide range of functionalities, making it suitable for programmable and parallel synthesis. The chemistry is modular, high-yielding, and operates under mild conditions. It has been successfully applied in various practical syntheses, including late-stage functionalization of natural products, peptide modifications, and DNA-encoded library synthesis. A machine learning model (SeNEx-ML) was also developed to predict reaction yields with high accuracy.

Highlights

• Development of a novel Se-N exchange chemistry between benzoselenazolones and boronic acids.
• The reaction is highly selective, modular, and high-yielding, with 95% of 485 examples achieving yields or conversions exceeding 70%.
• Compatibility with diverse functionalities and orthogonal to other top reactions in medicinal chemistry.
• Successful application in late-stage functionalization, peptide modification, and DNA-encoded library synthesis.
• Establishment of a machine learning model (SeNEx-ML) for reaction yield prediction with high accuracy.

Conclusion

In summary, we have successfully designed and developed an unprecedented highly selective and multi-orthogonal SeNEx chemistry between benzoselenazolones and boronic acids. This chemistry features modular, predictable, robust, and high-yielding characteristics, performed under mild and switchable reaction conditions. It demonstrates exceptional chemo-selectivity and functional group tolerance, enabling orthogonal synthesis with other established reactions. The practical applications in late-stage modification, peptide ligation, and DNA-encoded library synthesis highlight its potential in multidisciplinary fields. The establishment of the SeNEx-ML model further enhances its utility by predicting reaction outcomes accurately. This chemistry serves as a powerful tool to bridge the selenium chemical space with the existing chemical world, offering transformative potential in synthetic chemistry, material science, chemical biology, and medical chemistry.

Edith van der Nol ,  Nils Alexander Haupt ,  Qing Qing Gao ,  Benthe A. M. Smit ,  Martin Andre Hoffmann ,  Martin Engler-Lukajewski ,  Marcus Ludwig ,  Sean McKenna ,  J. Miguel Mata ,  Olivier J. M. Béquignon ,  Gerard van Westen ,  Tiemen J. Wendel ,  Sylvie M. Noordermeer ,  Sebastian Böcker ,  Sebastian Pomplun

Nature Communication

DOI: 10.1038/s41467-025-65282-1

Abstract

Affinity-selection platforms are powerful tools in early drug discovery, but current technologies – most notably DNA-encoded libraries (DELs) – are limited by synthesis complexity and incompatibility with nucleic acid-binding targets. We present a barcode-free self-encoded library (SEL) platform that enables direct screening of over half a million small molecules in a single experiment. SELs combine tandem mass spectrometry with custom software for automated structure annotation, eliminating the need for external tags for the identification of screening hits. We develop efficient, high-diversity synthesis protocols for a broad range of chemical scaffolds and benchmark the platform in affinity selections against carbonic anhydrase IX, identifying multiple nanomolar binders. We further apply SELs to flap endonuclease 1 (FEN1) – a disease related DNA-processing enzyme inaccessible to DELs – and discover potent inhibitors. Taken together, screening barcode-free libraries of this scale all at once represents an important development, enables access to novel target classes, and promises substantial impact on both academic and industrial early drug discovery.

Summary

This article introduces a barcode-free self-encoded library (SEL) platform for affinity selection-based hit discovery in early drug discovery. The SEL platform leverages tandem mass spectrometry and custom software for automated structure annotation, eliminating the need for external tags. The platform enables the screening of large libraries with diverse scaffolds, identifying high-affinity binders for targets like carbonic anhydrase IX and inhibitors for flap endonuclease 1 (FEN1). This approach overcomes limitations of DNA-encoded libraries (DELs) by avoiding synthesis complexity and incompatibility with nucleic acid-binding targets, offering a streamlined workflow for rapid hit discovery.

Highlights

1. A barcode-free self-encoded library (SEL) platform enables screening of over half a million small molecules in a single experiment.
2. SELs combine tandem mass spectrometry with custom software for automated structure annotation, eliminating the need for external tags.
3. Efficient, high-diversity synthesis protocols are developed for a broad range of chemical scaffolds.
4. The platform identifies multiple nanomolar binders for carbonic anhydrase IX and potent inhibitors for flap endonuclease 1 (FEN1).
5. SELs offer advantages in synthesis complexity and scope compared to DNA-encoded libraries (DELs), expanding the accessible chemical space for drug discovery.

Conclusion

The SEL platform represents a significant advancement in early drug discovery by enabling the screening of large, diverse libraries without the need for external tags. This barcode-free approach overcomes limitations associated with DNA-encoded libraries, such as synthesis complexity and incompatibility with nucleic acid-binding targets. The successful identification of high-affinity binders and inhibitors for challenging targets like carbonic anhydrase IX and flap endonuclease 1 demonstrates the platform's potential for rapid hit discovery. The streamlined synthesis and automated decoding capabilities of SELs make this technology accessible to a broader range of researchers, promising substantial impact on both academic and industrial drug discovery efforts. Future work will focus on further optimizing the platform for even larger libraries and exploring its application to additional challenging targets.

Alice R. Wong

ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00356

Abstract

DNA-encoded libraries (DELs) have revolutionized hit identification in drug discovery by offering an accessible, versatile, and cost-effective alternative to traditional high-throughput screening (HTS). This perspective analyzes the results of recent DEL technology (DELT) screens (2020−2025) to enable medicinal chemistry programs, focusing on case studies where active series were generated from DEL and distills key learnings and design principles for productive library construction. A notable trend is the productivity of 2-cycle DELs, which, despite their smaller size, consistently yield hits and have superior physicochemical properties compared to 3-cycle DELs. The criteria for inclusion are where DEL provided a medicinal chemistry series, defined by off-DNA hit resynthesis, profiling in relevant assay(s), and follow-up SAR optimization.

Summary

This article provides an in-depth analysis of the design and application of DNA-encoded libraries (DELs) in medicinal chemistry. It examines recent case studies (2020−2025) where DELs have been successfully used to generate active series for drug discovery. Key learnings include the effectiveness of 2-cycle DELs in yielding hits with better physicochemical properties compared to 3-cycle DELs. The article also explores various DEL designs, including linear, branched, and heterocycle-formation designs, and highlights the importance of physicochemical properties in hit identification. The study concludes that while there is no clear correlation between DEL size and productivity, 2-cycle libraries have shown significant promise in generating high-quality hits.

Highlights

• DNA-encoded libraries (DELs) offer a powerful alternative to traditional high-throughput screening (HTS) for hit identification.
• Recent case studies (2020−2025) demonstrate the effectiveness of DELs in generating active series for medicinal chemistry.
• 2-cycle DELs, despite their smaller size, consistently yield hits with superior physicochemical properties compared to 3-cycle DELs.
• Key physicochemical properties, such as molecular weight (MW), topological polar surface area (TPSA), and hydrogen bond donors (HBD), are critical in library design.
• The article emphasizes the importance of well-established on-DNA chemistry and standard building block classes in generating diverse and high-quality DELs.

Conclusion

The analysis of recent DEL technology screens highlights the potential of 2-cycle DELs in generating high-quality hits with desirable physicochemical properties. While there is no clear correlation between library size and productivity, 2-cycle libraries have shown significant promise. The study underscores the importance of physicochemical properties in hit identification and the effectiveness of well-established on-DNA chemistry and standard building block classes in library design. Future DEL designs should continue to leverage these principles to accelerate drug discovery.

Susmith Mukund

Structural Dynamics

DOI: 10.1063/4.0001022

Abstract

The methyl thioadenosine phosphorylase (MTAP) gene which is proximal to the CDK2N2A tumor suppressor gene on chromosome locus p23q is frequently deleted in ∼15% of cancer cells. This results in the accumulation of methylthioadenosine (MTA), which competes with S-adenosyl methionine (SAM), the methyl donor for the essential enzyme, protein arginine methyltransferase 5 (PRMT5). PRMT5 is thereby put in a hypomorphic state in these MTAP-deleted cancer cells, presenting an opportunity for its further inhibition with MTA-cooperative inhibitors. DNA- encoded library screening produced hits that cooperatively bound PRMT5:MEP50 and MTA. Optimization of these compounds and structural enablement through both crystallography and cryo-electron microscopy led to the discovery of AMG 193.

Crystal structure shows AMG 193 occupying the peptide binding site of the PRMT5 catalytic domain, where the R3 of the peptide substrate binds during the catalytic cycle, and in the vicinity of the co-inhibitor MTA (see figure, PDB id: 9C10). The tricyclic dihydrofuro- naphthyridine warhead mimics the R³ of the substrate with similar interactions, its amino-heterocyclic moiety forming salt bridge with E⁴⁴⁴ acid and a H-bond with the backbone carbonyl of E⁴³⁵, the furan oxygen in a H-bond with K³³³. The amino-heterocycle is in a displaced π:π stacking between W⁵⁷⁹ and F³²⁷, as well as van der Waals contact with residue Glu⁴³⁵, and MTA, a key feature of the MTA cooperative nature of the inhibitor. AMG 193 is further stabilized by a H-bond between its amide carbonyl, which is perpendicular to the tricyclic core, and the backbone amide of F⁵⁸⁰. The morpholine substituent adopts an axial conformation relative to tricyclic warhead. The terminal trifluoro-phenyl is packed in the very hydrophobic distal end of the substrate pocket, F⁵⁸⁰ in a π:π stack and Y304 in an edge-to-face stack with the phenyl ring of the ligand. The structure further explains why AMG 193 is MTA-cooperative and not synergistic with SAM.

Orville Pemberton, Amanda M Nevins, Thomas E Frederick, Emily Nicholl, Myron Srikumaran, Jun Chen, Alla Korepanova, Vincent Stoll, Andrew Petros, Sujatha Gopalakrishnan, Justin Dietrich, Liliam Rios Cordero, David J Hardee, Teresa I Ng, Chaohong Sun

Structural Dynamics

DOI: 10.1063/4.0000814

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has devastated global health, revealing an urgent need for novel therapeutics. The papain-like protease (PLpro) is one of two proteases encoded by SARS-CoV-2, representing an attractive drug target due to its dual roles in viral replication and host immune suppression. We employed a DNA-encoded library (DEL) screen to reveal starting points for our PLpro hit discovery campaign. These efforts led to the identification of compound 1, a diarylmethanol-containing substructure with a unique binding mode that induces PLpro dimerization. Compound 1 demonstrates potent activities in both a biochemical ubiquitin-rhodamine and antiviral HeLa-ACE2 cell assays. An X- ray co-crystal structure of compound 1 bound to PLpro solved to 2.0 Å showed that two molecules of compound 1 glues two monomers of PLpro together via binding to the BL2 groove of one monomer and the Ubl/thumb domain of the other. Several molecular interactions were observed between compound 1 and PLpro including hydrophobic interactions and several hydrogen-bonds across both monomers. The molecular glue-like properties of compound 1 on PLpro were further validated in solution with analytical SEC and protein-detect 2D-NMR. Subsequent rounds of SAR led to compound 2, which has comparable biochemical and antiviral activities and demonstrated the same dimerization mechanism of PLpro as seen in a 1.8 Å X-ray co-crystal structure. In summary, we have identified a new series of PLpro inhibitors with a novel mechanism of SARS-CoV-2 inhibition, providing a promising start for the discovery of antivirals for treating COVID-19.