New strategies to enhance the efficiency and precision of drug discovery

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Фев. 11, 2025

Drug discovery plays a crucial role in medicinal chemistry, serving as the cornerstone for developing new treatments to address wide range of diseases. This review emphasizes significance advanced strategies, such Click Chemistry, Targeted Protein Degradation (TPD), DNA-Encoded Libraries (DELs), and Computer-Aided Design (CADD), boosting drug process. Chemistry streamlines synthesis diverse compound libraries, facilitating efficient hit lead optimization. TPD harnesses natural degradation pathways target previously undruggable proteins, while DELs enable high-throughput screening millions compounds. CADD employs computational methods refine candidate selection reduce resource expenditure. To demonstrate utility these methodologies, we highlight exemplary small molecules discovered past decade, along with summary marketed drugs investigational that exemplify their clinical impact. These examples illustrate how techniques directly contribute advancing chemistry from bench bedside. Looking ahead, Artificial Intelligence (AI) technologies interdisciplinary collaboration are poised growing complexity discovery. By fostering deeper understanding transformative this aims inspire innovative research directions further advance field chemistry.

Язык: Английский

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Evolution of chemistry and selection technology for DNA-encoded library

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(2), С. 492 - 516

Опубликована: Окт. 11, 2023

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and non-self-replicating phenotypes, generating a diverse world. In analogy with biological world, DEL world can evolve by using central dogma, wherein DNA replicates PCR reactions to amplify genetic codes, sequencing transcripts information, DNA-compatible synthesis translates into phenotypes. Importantly, is key expanding space. Besides, evolution-driven selection system pushes chemicals under selective pressure, i.e., desired strategies. this perspective, we summarized recent advances in synthetic toolbox panning strategies, which will shed light on drug discovery harnessing vitro evolution via DEL.

Язык: Английский

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Photochemistry in Medicinal Chemistry and Chemical Biology

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(6), С. 4322 - 4345

Опубликована: Март 8, 2024

Photochemistry has emerged as a transformative force in organic chemistry, significantly expanding the chemical space accessible for medicinal chemistry. Light-induced reactions enable efficient synthesis of intricate structures and have found applications throughout different stages drug discovery development processes. Moreover, photochemical techniques provide innovative solutions biology, allowing precise spatiotemporal activation targeted delivery. In this Perspective, we highlight already numerous remarkable even more promising future photochemistry chemistry biology.

Язык: Английский

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Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(15)

Опубликована: Фев. 12, 2024

Abstract Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage great importance expanding the toolbox. We report first selenium‐nitrogen exchange (SeNEx) reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which inspired by biochemical SeNEx Ebselen cysteine (Cys) residue Se−S). formed selenoalkyne connection readily elaborated, thus endowing this multidimensional diversity. Besides, modular, predictable, high‐yielding, features fast kinetics (k2≥14.43 M −1 s ), excellent group compatibility, works well at miniaturization (nanomole‐scale), opening up many interesting opportunities organo‐Se synthesis bioconjugation, as exemplified sequential (coupled ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) sulfur‐fluoride (SuFEx)), selenomacrocycle synthesis, nanomole‐scale Se‐containing natural product library DNA‐encoded (DEL), late‐stage peptide modification ligation, multiple functionalization proteins. These results indicated that useful developments, established will serve transformative platform in multidisciplinary fields such synthetic chemistry, material science, chemical biology, medical drug

Язык: Английский

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Recyclable Mesoporous Graphitic Carbon Nitride Catalysts for the Sustainable Photoredox Catalyzed Synthesis of Carbonyl Compounds

ACS Catalysis, Год журнала: 2023, Номер 13(20), С. 13414 - 13422

Опубликована: Окт. 3, 2023

The conversion of feedstock materials into useful chemical compounds through feasible processes is highly sought after from both industrial and environmental perspectives. In this study, we developed a simple scalable protocol for synthesizing aldehydes, ketones, amides abundant raw materials, such as alkanes, alkenes, carboxylic acids. Using photoactive mesoporous graphitic carbon nitride catalyst (mpg-CN) molecular oxygen, successfully transformed over 60 substrates in good yield selectivity. This method suitable the late-stage modification existing drug molecules their corresponding carbonyl derivatives can provide direct access to intermediates or oxidative decomposition degradation products important understanding biological pathways development. Additionally, our applicable large-scale preparation, mpg-CN be recycled without significant loss catalytic activity Comprehensive experiments, including labeled oxygen studies, support photo-oxidative mechanism.

Язык: Английский

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Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Science, Год журнала: 2024, Номер 384(6701), С. 1259 - 1265

Опубликована: Июнь 13, 2024

The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor purity resulting in suboptimal performance. In this work, we report technique to overcome issue through self-purifying release of the after magnetic bead-based synthesis. Both and last building blocks each assembled member were linked beads by tethers that could be cleaved mutually orthogonal chemistry. Sequential cleavage tether, with washing between, ensured final comprises only fully complete compounds. outstanding attained approach enables direct correlation display encoding, allows for an increased reaction scope, facilitates use more diversity elements while achieving greatly improved signal-to-noise ratios selections.

Язык: Английский

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Bioorthogonal Synthetic Chemistry Enabled by Visible‐Light Photocatalysis

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(47)

Опубликована: Авг. 13, 2024

Abstract The field of bioorthogonal chemistry has revolutionized our ability to interrogate and manipulate biological systems at the molecular level. However, range chemical reactions that can operate efficiently in environments without interfering with native cellular machinery, remains limited. In this context, rapidly growing area photocatalysis offers a promising avenue for developing new type tools. inherent mildness, tunability, chemoselectivity, external controllability photocatalytic transformations make them particularly well‐suited applications living systems. This minireview summarizes recent advances technologies, particular focus on their potential enable selective generation designed products within biologically relevant or settings.

Язык: Английский

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Visible light-induced chemoselective 1,2-diheteroarylation of alkenes

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 19, 2024

Abstract Visible-light photocatalysis has evolved as a powerful technique to enable controllable radical reactions. Exploring unique photocatalytic mode for obtaining new chemoselectivity and product diversity is of great significance. Herein, we present photo-induced chemoselective 1,2-diheteroarylation unactivated alkenes utilizing halopyridines quinolines. The ring-fused azaarenes serve not only substrate, but also potential precursors halogen-atom abstraction pyridyl generation in this photocatalysis. As complement metal catalysis, process with mild redox neutral conditions assembles two different heteroaryl groups into regioselectively contribute broad substrates scope. obtained products containing aza-arene units permit various further diversifications, demonstrating the synthetic utility protocol. We anticipate that protocol will trigger advancement alkyl/aryl halides activation.

Язык: Английский

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Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(35), С. 24638 - 24653

Опубликована: Авг. 22, 2024

Identifying biologically active ligands for membrane proteins is an important task in chemical biology. We report approach to directly identify small molecule agonists against by selecting DNA-encoded libraries (DELs) on live cells. This method connects extracellular ligand binding with intracellular biochemical transformation, thereby biasing the selection toward agonist identification. have demonstrated methodology three proteins: epidermal growth factor receptor (EGFR), thrombopoietin (TPOR), and insulin (INSR). A ∼30 million a 1.033 billion-compound DEL were selected these targets, novel subnanomolar affinity low micromolar cellular activities been discovered. The INSR activated possibly allosteric site, exhibited clear synergistic effects insulin, downstream signaling pathways. Notably, did not activate insulin-like 1 (IGF-1R), highly homologous whose activation may lead tumor progression. Collectively, this work has developed "functional" selections cell surface provide widely applicable discovery proteins.

Язык: Английский

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Comparative Study of DNA Barcode Integrity Evaluation Approaches in the Early-Stage Development of DNA-Compatible Chemical Transformation

ACS Pharmacology & Translational Science, Год журнала: 2023, Номер 6(11), С. 1724 - 1733

Опубликована: Окт. 12, 2023

DNA-encoded libraries (DEL) have emerged as an important drug discovery technical platform for target-based compound library selection. The success rate of DEL depends on both the chemical diversity combinatorial and accuracy DNA barcoding. Therefore, it is critical that chemistry applied to construction should efficiently transform a wide range substrates while preserving integrity tags. Although several analytical methods been developed measure damage caused by reactions, efficient cost-effective evaluation criteria detection are still demanding. Herein, we set standards evaluating compatibility development at laboratory level. Based four typical models three different formats, evaluated capabilities methods, including ultraperformance liquid chromatography (UPLC-MS), electrophoresis, quantitative polymerase chain reaction (qPCR), Sanger sequencing. This work systematically revealed scope capability in assessing damages transformation. results, recommended UPLC-MS qPCR barcode analysis early-stage DNA-compatible chemistry. Meanwhile, identified sequencing was unreliable assess this application.

Язык: Английский

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