Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• , de novo peptide binder generation, diffusion models for generating novel small molecule scaffolds, and deep-learning predictors of binding affinity to rapidly triage candidates. Keywords: diffusion models; drug discovery; generative AI; peptides; small molecules; Introduction In drug discovery

• screen of monocyclic peptides [8]. As an alternative to optimising peptide-based molecules, knowledge of key binding interactions exhibited by potent peptide binders can be leveraged to inform small-molecule design. The field of peptidomimetics seeks to design small molecules that mimic the binding mode

• fails to yield hits [9]. While the term peptidomimetics has been used to describe a variety of molecular classes, including modified peptides and molecular scaffolds for display of amino acid side-chains, this Perspective focuses on non-peptidic small molecules with the appropriate shape and

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• ]. This event-driven mode of action enables catalytic turnover, can reduce off-target toxicities associated with high inhibitor doses, and does not require a deep or well-defined binding pocket, allowing potential access to targets considered “undruggable” by conventional small molecules [8]. In 2018, a

Electrosynthetic access to unsymmetrical oxaza[8]helicenes with high chiral stability and strong circularly polarized luminescence (CPL)

• Tin Zar Aye,
• Rubal Sharma,
• Muthu Karuppasamy,
• Daiya Suzuki,
• Haruka Nakajima,
• Yoshitane Imai,
• Mitsuhiro Arisawa,
• Mohamed S. H. Salem and
• Shinobu Takizawa

Beilstein J. Org. Chem. 2026, 22, 372–382, doi:10.3762/bjoc.22.25

• ; electrochemistry; emission; helical elongation; helicene; photophysical; Introduction Chirality is a pervasive feature of natural and artificial systems, and chiral small molecules continue to underpin advances in chemistry and materials science [1][2]. Among them, helicenes – ortho-condensed polycyclic aromatic

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• observed for these annulated molecules, while their analogous non-annulated control compounds were not bioactive. Keywords: annulation; arenes; antimicrobials; fused-ring systems; UV–vis spectroscopy; Introduction Polycyclic aromatic heterocycles are a diverse class of small molecules with utility in a

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• approved drug on the market), Tchem (chemistry, known to bind to small molecules with high potency), Tbio (biology, kinases that have notably gene ontology leaf term annotations associated with disease and cellular role but lack associations with bioactive molecules) to the less explored Tdark (dark genome

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• level of oxygen content in biomass, small molecules arising from biomass often possess a carbonyl group. This is why biobased platform molecules possessing a carbonyl group, either under the form of an aldehyde, a ketone, an acid or an ester, play a dominant role in biobased chemistry. This review aims

Solar thermal fuels: azobenzene as a cyclic photon–heat transduction platform

• Jie Yan,
• Shaodong Sun,
• Minghao Wang and
• Si Wu

Beilstein J. Org. Chem. 2025, 21, 2036–2047, doi:10.3762/bjoc.21.159

• azobenzene small molecules into polymer fibers [65], enabling solvent-free charging and discharging under visible light (Figure 6a). This material exhibited good capacity for releasing high-temperature heat (80–95 °C) at room temperature and in cold environments, along with an energy storage lifetime

• approaching two years, significantly exceeding the reported storage lifetime of other azobenzene-based solar thermal fuels. Han et al. synthesized a series of bisazobenzene small molecules with various substituents [90], all exhibiting photoinduced solid–liquid phase transitions. In contrast, comparable

• monoazobenzene small molecules showed substituent-dependent photoinduced solid–liquid phase transition behavior. This provides a feasible strategy for enhancing the energy density of azobenzene-based solar thermal fuels by controlling phase transitions (Figure 6b). Wu et al. conducted a comparative study on

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• , Biomedical Sciences Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK 10.3762/bjoc.21.150 Abstract The value of small molecules that chemically modify proteins is increasingly being recognised and utilised in both chemical biology and drug discovery. The discovery of such chemical tools

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• . Electrochemical studies Alkylating agents are widely recognized for their ability to form covalent bonds with biological macromolecules (proteins, DNA). The literature discusses the interaction of small molecules with proteins, highlighting how linear sweep voltammetry (LSV) can be used to understand these

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• ][22]. These attributes allow us to construct MOF-based catalysts with active sites that are isolated within cavities of the same size range as small molecules and whose walls are decorated with precisely located functional groups. We can rationally elaborate these functional groups to modulate

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• down by the highly acidic environment of tumor cells, which acts as an exogenous or endogenous stimulus to enable the controlled release of the encapsulated drugs. These nanosystems are highly compatible with the body and comprise biocompatible, water-dispersible, and low-toxicity small molecules. 2.2

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• target binding will incur little entropic cost) and high selectivity (since off-target interactions will be minimised) [1]. There are several methods by which the conformations of small molecules can be controlled, but in this review we will focus upon one particular method, which is the installation of

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• invention of the bioactivity-guided fractionation (BGF) workflow by Selman Waksman to search systematically for new bioactive small molecules (Figure 1) [11]. He believed that the fungus Penicillium rubens produces penicillin to suppress the growth of other microorganisms, especially those it competes with

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• rotaxane-based small molecules and polymer material prevents their further development. Based on the foregoing, the precise control of the structures of small molecules, which applies to polymer systems, is highly desired to implement an elaborate structure–property control in rotaxane-based polymer

• first [63]. In such structural-regulation development in the polymer system, the approach has been different from that for small-molecule systems probably because of the synthetic complications involved in implementing the structural control for small molecules to the polymer system. In 2001, Li and co

• polymer architectures with defined structures. In summary, the structural-regulation method for CD-based rotaxanes displays a clear trend: (1) precise control but complicated framework on small molecules, and (2) easy process but challenging control on polymer systems. To overcome this trade-off, a new

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• colleagues [1]. These compounds, which feature a Lewis acid (LA) and a Lewis base (LB), whose interaction is hindered by bulky substituents or chain strain, have garnered significant attention. Initially explored for their ability to trap small molecules [2][3], such as H2 [4], CO2 [5][6][7], N2O [8][9], and

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

• utilise the self-assembly of small molecules into a network of long anisotropic structures which can entangle or cross-link. This network can immobilise the solvent, resulting in a material with both solid-like and liquid-like characteristics. The versatility of these compounds arises from their self

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• , the first step is to identify the missing component, which can be facilitated by atom-mapping packages [84][85][86][87] that assign a unique label to each atom in the reactants and products. With the atom-mapping information, one can apply the rule-based method, CGRTools [88], to add small molecules

• ]. Moreover, predicting reaction conditions can help optimize the synthetic route [183] by providing the necessary information for each synthetic step. Coley et al. [12] integrated ASKCOS [184], an automated CASP software, with the self-driving lab [185] and demonstrated the synthesis of 15 small molecules

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• Andreas Wiest Pavel Kielkowski LMU Munich, Department of Chemistry, Butenandtstr. 5-13, 81377 Munich, Germany 10.3762/bjoc.20.199 Abstract Identification of interactions between proteins and natural products or similar active small molecules is crucial for understanding of their mechanism of

• acid, base, or redox-labile parts of the linker [52]. Most recently, Wozniak et al. mapped the binding sites of a large small molecules library, which were equipped with a photo-crosslinker [110]. The study used the acid-cleavable dialkoxydiphenylsilane (DADPS) linker to release the probe–peptide

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• drug-like compounds with synthetic ease [5][6]. In recent years use of deuterium in drug discovery has expanded beyond mechanistic and tracer studies to deuterium incorporation in small molecules in attempts to hijack the deuterium kinetic isotope effect to induce longer drug t1/2 and greater systemic

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• applications in organic chemistry. Keywords: asymmetric synthesis; catalyst recycling; heterogenisation; organocatalysis; solid support; Introduction Organocatalysts are small molecules that do not contain a metal atom in the reaction centre and are able to increase the speed of reactions. They have proven

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• the field of computational chemistry and bioinformatics. It is extensively used to model and simulate the dynamic behaviour of various molecular systems, including proteins, nucleic acids, lipids, and small molecules. GROMACS provides various tools for system preparation, simulation setup, and post

• interaction interfaces with other proteins, nucleic acids, lipids, small molecules, and ions, starting from a protein structure. PeSTo-Carbs is specifically trained to predict carbohydrate and cyclodextrin binding interfaces on proteins. Two different modules are available: a general model PS-G for a wide

• be used for this purpose, although here are listed free docking tools: 1. Autodock [120][121]: It is a suite of advanced docking tools used for predicting how small molecules, such as drug candidates or substrates, interact with known 3D protein structures. It offers two generations of software

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• falls between small molecules and large biologicals such as antibodies. Small molecules typically weigh less than 900 Dalton (Da), while the molecular weight of large biologicals ranges from approximately 5,000 to 150,000 Da. Although some small RiPPs may be classified as small molecules, the majority

• proteins allows peptides to disturb protein–protein interactions, which is a challenging task for small molecules. The principles of RiPP biosynthesis make the RiPP technology an ideal platform for the generation of designed peptides and allow tailored derivatisation of these peptides. The RiPP technology

• regeneration systems have been widely applied to small molecules [28][29][30], as well as polyketide natural products [31], and RNA [32]. To the best of our knowledge, these systems have not yet been applied to peptide natural products. By providing a comprehensive overview of the various methylation options

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• efficient strategies for accessing functionalized pyrazole derivatives. Thio/selenocyano groups are widely existing in the core structural motifs of various natural products and pharmaceutical agents [16][17][18][19][20]. Many S/SeCN-containing bioactive small molecules have been proved to possess wide