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

• . There are many AI tools for general ligand-based drug design under active development, spanning a range of generative architectures (e.g., variational autoencoders, generative adversarial networks). Here, we specifically highlight the potential of using diffusion-based models for generating small

• protein–ligand dataset (from Binding MOAD [51]) to factor in the constraints of typical binding pockets. ShEPhERD is an interaction-aware diffusion model developed by Coley and co-workers that is capable of bioisosteric fragment merging [39]. For fragment merging, the model was trained on a subset from

• discovery tools that are ligand-agnostic are under development, along with small molecule prediction methods that do not require experimental data on target-specific peptide binders. Nevertheless, we envisage that given the ease of binder design and screening, synthetic accessibility, and in vitro assay

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• the conformation of the ternary complex through the strategic modification of the POI ligand, the linker, and the E3 ligase ligand. Several studies have successfully utilized this strategy to enhance disease treatment outcomes via the PROTAC technology [22][28][29]. The rapid progression of the PROTAC

• ][36]. Accordingly, this review emphasizes the advantages of PROTACs in achieving high selectivity among homologous proteins. We systematically summarize the correlations between PROTAC structural components, specifically the POI ligand, the linker, and the E3 ligand, and their role in dictating

• Influence of linkers on the selectivity of PROTACs in highly homologous protein families As previously established [37], a PROTAC molecule comprises three essential components: a POI ligand, a linker, and an E3 ligand. In drug design, POI ligands are typically derived from FDA-approved small-molecule

Hydrogen production from formic acid catalyzed by NHC–Cu complexes

• Orlando Santoro and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2026, 22, 620–627, doi:10.3762/bjoc.22.48

• have also been explored. Beller and co-workers reported the first Fe catalyst bearing a phosphine ligand able to produce H2 with a TON of 1942 in the absence of additives [32]. A well-defined pincer–Fe complex allowing FA decomposition was reported by Milstein and co-workers [33]. While high TONs (up

• 3 hours (Table 1, entry 2). Indeed, this complex proved to be three times more efficient than CuI, the best catalyst identified for this transformation in previous studies [44]. By replacing the chloride ligand with iodine, the conversion drastically decreased (Table 1, entry 4). The same effect was

• observed by using complexes bearing an NHC ligand with N-alkyl substituents or a saturated backbone (Table 1, entries 5 and 6). Finally, the effect of the bulkiness of the ligand was investigated. In the presence of [Cu(Cl)(IPr*)] (5) bearing a sterically demanding NHC, 36% conversion was achieved while

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

• conjugating a CAM4066-derived warhead to CRBN or VHL ligands, four VHL-recruiting PROTACs, were prepared using PEG and alkyl linkers, alongside two CRBN-recruiting analogues featuring constrained linkers. A ligand–linker analogue in which a linker is projected from the solvent-exposed region of CK2α retained

• adjacent to the ATP-binding site of CK2α [5][6]. Fragment-based ligand discovery subsequently enabled the development of CAM4066, a selective inhibitor that simultaneously engages the αD and ATP sites. CAM4066 validated the αD region as a tractable and selective binding pocket for CK2 kinase inhibition

• conjugated CAM4066-derived ligands to both CRBN or VHL E3-ligase recruiters. We created VHL-recruiting PROTACs for CK2 using PEG and alkyl linkers, while the CRBN-recruiting analogues featured more constrained linkers. A ligand–linker analogue bearing a linker projected from the solvent-exposed region of the

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• growth factor receptor 2 (FGFR2) to overcome the issues of drug resistance and adverse reactions associated with traditional inhibitors in the treatment of FGFR2-driven tumors. Erdafitinib was employed as the targeting ligand, and its aliphatic amine site was conjugated with a CRBN E3 ligase ligand to

• proper ligand binding, thus promoting uncontrolled cell proliferation [11][14]. Mutations in FGFR2 may alter its structure, enabling it to bypass normal regulatory mechanisms and activate downstream oncogenic pathways independently of external stimuli, which also contributes to tumor development. Gene

• Discussion FGFR2-targeted degrader design PROTAC molecules are composed of three key elements: a specific ligand targeting the protein of interest (POI), a recruiter for an E3 ubiquitin ligase, and a linker that covalently connects these two functional moieties into a single molecular entity [29]. Herein, we

Kinetic resolution of racemic planar-chiral vinylcymantrenes by molybdenum-catalyzed asymmetric metathesis dimerization

• Haruna Imazu,
• Hitoshi Izu,
• Yasuhiro Ohki and
• Masamichi Ogasawara

Beilstein J. Org. Chem. 2026, 22, 568–574, doi:10.3762/bjoc.22.42

• )/kinetic resolution (KR) of racemic planar-chiral vinylcymantrene derivatives rac-1a–c The vinylcymantrene substrates, rac-1, prepared as above are planar-chiral due to the presence of an unsymmetrically substituted η5-(1-R-2-vinylcyclopentadienyl ligand (R = Br, Me, or I). The racemic substrates were

• benzene at the indicated temperature in the presence of an appropriate chiral Mo-precatalyst (10 mol %), which was generated in situ from the Mo-precursor, (pyrrolyl)2Mo(=CHCMe2Ph)(=N-C6H3-2,6-iPr2) [36], and an axially chiral biphenol ligand. The chiral Mo/(R)-L1 precatalyst [21] facilitated the

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• Lys-121 to alanine in the survivin protein resulted in a drastic loss of binding affinity (WT 120 nM to K121A 22 µM) for the new ligand (Figure 3). We conclude that the new tweezer conjugate specifically directs its tweezer moiety to Lys-121 and thus reinforces the H3–survivin peptide–protein

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• , Nicolaou and co-workers merged both building blocks within a Ni(II)/Cr(II)-catalyzed NHK reaction using chiral ligand 206 (Scheme 23) [95]. Upon treatment with DBU, 3-methylenetetrahydrofuran 201 was obtained in 56% yield over two steps. PMB-deprotection, iodination and selective reduction of the ester

• coupling between aldehyde 292 and iodide 296 with ligand 172 (see Scheme 17) was used for the assembly of 297 (Scheme 34). The addition of KHMDS induced the cyclization towards tetrahydropyran 298. Finally, oxidation of the sulfide moiety afforded sulfone 299. Using this synthetic strategy, Kim and co

Synthesis and uranyl(VI) extraction performance of a calix[4]pyrrole–tetrahydroxamic acid receptor

• Sara Karnib,
• Rana Baydoun,
• Wissam Zaidan,
• Nancy AlHaddad,
• Omar El Samad,
• Bilal Nsouli,
• Francine Cazier-Dennin and
• Pierre-Edouard Danjou

Beilstein J. Org. Chem. 2026, 22, 486–494, doi:10.3762/bjoc.22.36

• , removing up to 95% of uranyl(VI) from aqueous solutions (1 mM) at acidic pH, likely due to the strong coordination provided by its hydroxamic acid groups. Further studies revealed that the extraction efficiency also depends on the ligand-to-metal molar ratio. These findings establish PCP HA as a promising

• spectroscopy. The extraction performance was systematically evaluated as a function of pH and ligand-to-metal molar ratio to study the effect of these two key parameters on the extraction process. In doing so, this work aligns with current research dedicated to the design of functional supramolecular materials

• corresponding hydroxamic acid, with no detectable acid-derived by-products. Solubility tests revealed that PCP HA is soluble exclusively in highly polar aprotic solvents (DMSO, DMF) and remains completely insoluble in other common organic solvents (chloroform, ether, etc.) and water. The absence of ligand

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• , Hayashizaki, and Ito reported a highly stereoselective asymmetric cross-coupling reaction of 2-methylnaphthylmagnesium bromide with bromonaphthalene, catalyzed by a nickel complex with ferrocenylphosphine as the ligand, successfully synthesizing biaxially chiral molecules, namely 1,1':5',1"- and 1,1':4',1

• ligands (Scheme 3) [44]. The resulting catalysts 18 demonstrated remarkable efficiency in the asymmetric transfer hydrogenation of quinoline derivatives. Along similar lines, Zhang and co-workers introduced an additional axial chirality element into a ligand framework, affording a pair of diastereomeric

• potential applications in ligand and catalyst development. In a complementary direction, Smith’s group achieved the highly enantioselective synthesis of axially chiral naphthamides (Scheme 6) [47]. Their strategy employed transition-state hydrogen bonding to induce substrate deracemization, followed by

A facile and practical method for the synthesis of trans-(±)-taxifolin and its derivatives via Darzens reaction

• Bo Peng,
• Panpan Yang,
• Maaz Khan,
• Xiaotong Lin,
• Jiang Wu,
• Peng Fu and
• Qingqing Wu

Beilstein J. Org. Chem. 2026, 22, 443–450, doi:10.3762/bjoc.22.31

• readily available. Additionally, Xiang et al. [17] and Jew et al. [18] reported asymmetric syntheses of taxifolin, which suffer from long-step operation and the use of complicated and expensive metal-ligand catalysts. Currently, the most widely used chemical method is the synthesis of trans-(±)-taxifolin

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• cancer cell line. Molecular docking simulation revealed strong binding interaction and affinities towards the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and the protein–ligand interaction resembles the interaction found in the co-crystallised protein–erlotinib complex. Result and

• -covalent interactions with the target protein, has a significant impact on their anticancer potential. The binding interactions of compounds 7 and 8 with the active (1M17) and inactive (4JHO) EGFR tyrosine kinase domain are summarised in Table 2. The ligand structure of compound 7 was obtained from a

• single-crystal XRD coordinate file, whereas the structure of compound 8 was derived from DFT energy minimisation. Both ligand structures were converted into PDB format for molecular docking studies using the crystal structures of EGFR tyrosine kinase in active conformation (1M17) and inactive

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• was required to complete the cycloaddition), an even lower isolated yield of calixarene 37 (≈35%) was observed, indicating that a large portion of Cu+ was complexed with the calixarene product when no excess competing ligand such as triethylamine was present in the reaction mixture. Following our

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• distinct mechanistic pathways, a simplified version of which is described herein. The active catalytic species, palladium(II) pivalate, is formed in situ from Pd(COD)Cl₂ through ligand exchange with pivalic acid (PivOH). Complexation of this active Pd(II) species with ligand L1 and the amide substrate

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• ][41]. They contain an iron-protoporphyrin core with a cysteine ligand [42] in the axial position, which cycles through different oxidation states (Fe3+/Fe2+/Fe4+) to form highly reactive oxo species which are effective at abstracting closely positioned aliphatic hydrogens via HAT (hydrogen atom

• included [48][49]. These enzymes exhibit distinctly different Fe-containing active sites, typically consisting of two histidines, a carboxylate ligand (e.g., aspartate) and, of course, the ketoglutarate which is bound both via the C-2 ketone and C-1 carboxylate to form 1 (Scheme 1C). Upon its coordination

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• and nucleotide, DNaze I-binding). The structure of the 8DNH protein was retrieved from the protein data bank and the Molegro Virtual Docker 6.0 software was used to prepare it for the docking study [66][67]. The pose organizer and the ligand energy inspector tool were used to examine the docking

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• Taube reported the now famous pentaammineosmium(II) η2-benzene complex: the first system to yield kinetically stable η2-arene complexes that resist ligand exchange at room temperature in solution (Figure 5) [48]. This breakthrough opened the door to the isolation of such complexes and their subsequent

• exposure to reaction conditions that more labile systems could not tolerate. Crucially, most reagents used in organic synthesis react preferentially with the arene ligand rather than the metal center [45]. Building on the electronic blueprint established by the osmium system, Harman introduced a new

• , display remarkable substitution inertness, even toward strong π-acids and good σ-donors. The substitution rate being relatively independent of the incoming ligand is consistent with a dissociative substitution mechanism. Typically, coordination occurs at positions that minimally disrupt the arene π-system

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• intrinsic stereoelectronic preferences but also by intermolecular interactions within the ornithine decarboxylase active site. Therefore, the conformational behavior of DFMO arises from a delicate balance between the fluorine gauche effect and the intermolecular interactions that stabilize the ligand–enzyme

• decarboxylase from Leishmania infantum complexed with PLP and DFMO, the bound ligand corresponds instead to human arginase I (PDB code 3GN0). While binding to arginase I is not related to DFMO’s pharmacological activity, both enzymes recognize ornithine-related substrates, allowing DFMO to occupy the arginase

• amino acid residues and water molecules, while the ligand is delineated by a contour line to distinguish it from the binding cavity. Lowest-energy type-I, type-II, and type-III conformers of the zwitterionic form of (S)-DFMO. Color labels: H = blue, C = pink, N = orange, O = red, F = yellow. DFT

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• corresponding amine followed by N-tosylation, providing product 10 in 63% yield without altering the enantiomeric excess (Scheme 4). Additionally, product 8g was converted into the chiral phosphine ligand 12 while fully preserving its helical chirality and successfully applied in palladium-catalyzed

• [5]helicenes. Scale-up synthesis and post-synthetic application of chiral helical product 8g. Post-synthetic transformation of product 8g to chiral phosphine ligand 12 and its application in Pd-catalyzed reactions. Acknowledgements The authors acknowledge the CSIR-IHBT, Palampur for providing

Improved synthesis and physicochemical characterization of the selective serotonin 2A receptor agonist 25CN-NBOH

• Adrian G. Rossebø,
• Hannah G. Kolberg,
• Anders E. Tønder,
• Louise Kjaerulff,
• Poul Erik Hansen,
• Karla A. Frydenvang,
• Jesper Østergaard and
• Jesper L. Kristensen

Beilstein J. Org. Chem. 2026, 22, 175–184, doi:10.3762/bjoc.22.11

• ], enhancement of cognitive flexibility [9], induction of neuroplasticity in cortical neurons [10], and persistent antidepressant-like effects [11]. Given the widespread use of this ligand in basic research, some scattered data on its physicochemical properties are available, but a structured and comprehensive

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• chiral platinum(II) complex was synthesized via Sonogashira coupling and subsequent coordination of a pincer ligand to a precursor. The complex exhibited a broad absorption band ranging from 250 to 550 nm in the UV–vis spectrum, with TD-DFT calculations indicating mixed ligand-to-ligand charge transfer

• (LL’CT) and metal-to-ligand charge transfer (MLCT) character. Photoluminescence measurements in CH2Cl2 solution revealed dual emission peaks at 427 nm and 596 nm, with a quantum yield of 3%. In PMMA matrix, the emission peaks were blue-shifted to 408 nm and 558 nm, and the quantum yield slightly

• and synthesis of a chiral ligand featuring an axially chiral binaphthyl backbone and its employment in the construction of novel types of a chiral platinum(II) complex with pincer ligand (Figure 1). We investigated the spectroscopic properties of the resulting complex, including its chiroptical

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• saturation the aromatic ring facilitates synthetic chemists to efficiently synthesize natural products with complex three-dimensional structures. Recent advances in catalyst and ligand design have enabled unprecedented progress in the catalytic hydrogenation of (hetero)aromatic systems. Quinoline

• both homogeneous and heterogeneous systems, the hydrogenation of (hetero)arenes has become a cornerstone of modern synthesis for constructing saturated carbocycles and heterocycles [37]. When an appropriate ligand is paired with a transition-metal catalyst, stereoselective hydrogenation of aromatic

• catalyst and ligand design showcase complementary solutions to these selectivity issues, with each substrate class imposing its own opportunities on hydrogenation outcomes. With these considerations in mind, the following section categorizes catalytic hydrogenation strategies by arene substrate type and

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• corresponding vic-bis(dithiane) derivatives 16a–d. In 2018, Milsmann et al. reported the dimerization of benzyl bromide using a zirconium complex as a photosensitizer (Scheme 4) [14]. Heating a zirconium precursor with the pincer-type ligand 17, which can be synthesized in three steps from commercially

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• , catalyzed by a chiral copper complex generated in situ from CuTC and phosphoramidite ligand 361, furnished the corresponding enantioenriched alkenyl chlorides in high yield and with exclusive formation of the Z-isomer. A decade later, Fañanás-Mastral and co-workers demonstrated that alkenylcopper species

• , generated via borocupration of terminal alkynes, underwent allylic substitutions to furnish Bpin-substituted alkenyl chlorides in high enantioselectivity (Scheme 65B) [204]. Key to the transformation was the use of a sulfonate-substituted N-heterocyclic carbene ligand, introduced as its imidazolium salt

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• methyl ester who observed intramolecular proton transfer with partial incorporation of deuterium upon quenching with deuterium oxide. In a different context, the role of the Pd catalyst and the associated ligand was studied in the cross-coupling of the organozinc reagent ent-35 with 3-iodomethylfuran