Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• fluorescence quenching phenomena with aggregate-induced emission (AIE) in aqueous media. They synthesized a [2]rotaxane with one dithienylethene unit as a stopper, and one BAA and one urea binding site, as well as one DB24C8 macrocycle with a tetraphenylethene (TPE) fluorophore [16] (Figure 7). Addition of

• incorporation of functional hydrazone photoswitches into rotaxanes began more recently with Leigh. Thus, these photoswitches are underexplored in MIMs. Specifically, Leigh and co-workers synthesized [2]rotaxanes in which a pyridyl-acyl hydrazone moiety functioned as both photo- and thermal-switchable binding

• site, enabling precise control over molecular motion [71]. The incorporation of pyridyl-acyl hydrazone units is demonstrated to enable high binding (>95%) and reversible macrocycle shuttling between two binding sites (98%). Moreover, structural analysis revealed distinct intercomponent hydrogen-bonding

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

• , examination of the structure of CLK3 shows that this key lysine 241 is very close to the entry of the ATP binding site (Figure 1B). Lysine 241 could be considered as an opportunity to design new molecules with an improved affinity to CLK3, by adding specific interactions with this amino acid bearing a primary

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• the protein-binding site than the bent Z-isomer. However, it would be more desirable to have an inactive molecule in its most stable state which can be activated by irradiation [51][59]. Hernando and co-workers were able to design photoswitchable neurotransmitters of ionotropic kainate receptors by

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• ), whereas the second antenna can exert more or less favorable secondary binding effects at the periphery of the carbohydrate binding site, depending on the isomeric state. In order to rationalize these hypotheses, we commenced a molecular modeling study to inspect the different isomeric states of the tested

• Tyr137 flanking the carbohydrate binding site of FimH [47]. First, Glide [48] as part of the Maestro interface of the Schrödinger software package [49] was used to calculate docking scores (Table 3). More negative docking scores correlate with higher FimH affinity. In a second step, the best docking

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• -dimensional structure of the Pepper binding site with a bound HBC derivative (pdb code 7EOM). The hydrogen bond between N7 of guanine in position 41 (G41) and the hydroxy group of HBC is highlighted as gray dashed line [12]; d) concept for covalent attachment of HBC fluorophores to the N7 atom of G41 of the

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

• ][179][180][181]. For example, consider the analgesic drug fentanyl (104, Figure 11). This drug contains a piperidine moiety, which is protonated at physiological pH and forms a salt bridge with an aspartate residue in the binding site of the μ-opioid receptor. One of the drawbacks of fentanyl (104) is

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

• /building the protein and the ligand in their optimal conformation (as discussed above), ii) predicting the protein binding site; iii) modelling the ligand into the protein binding site, iv) assessing binding affinity through sampling and scoring, as discussed in the following paragraphs [103]. Prediction

• of the protein binding site Over the years, structure-, sequence-, and homology/template- based methods have been employed to identify and predict carbohydrate-binding sites starting from the protein structure [104]. Recently, thanks to the fast development of machine learning techniques, new

• ligands into fragments, places, and scores them quickly in the binding site. The best fragments are then assembled to form the complete ligand, optimizing the generated conformations. FlexX's strengths include rapid and efficient exploration of the conformational space, handling ligand flexibility, a

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• template, selecting the ligand building blocks with highest affinity and bringing them in proximity within the binding site. Building blocks are opportunely chosen to have complementary reactivity and therefore to react irreversibly within the binding site and assemble into the final ligand. Before the

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

• biocatalytic applications. The co-crystallisation of LahSB with bound SAH provides important details about the structure–function relationship, the substrate–enzyme interaction, and the cofactor binding site (Figure 5). This structural information, including the residues involved in binding, is essential for

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• has a tetrameric structure, displays a high affinity for ᴅ-galactose (ᴅ-Gal, with Kd = 34 μM) and galactosides. The 3- and 4-hydroxy function on the ᴅ-Gal unit are involved in the coordination of Ca2+ in the binding site [5][6][7][8][32]. A large range of galactosyl conjugates have been synthetized

• rather similar Kd values. In order to rationalize this difference in binding mechanism, molecular models were obtained for selected low-energy conformations of E- and Z-isomers of a “model” scaffold of the para-azobenzene derivative in the binding site of LecA (Figure 5), by simple superpositioning of

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• catalytic groove. The sequence logo of C0/C1-type KRs showed that some of them possess the catalytic Y (9), but such KRs instead possess mutation in NADPH binding site (Figure S3 in Supporting Information File 1). In C2-type KRs, we found that most C2-type KRs possessed the catalytic Y (9), but some

• either A2- or B2-KRs, but are likely to contain mutations in NADPH binding site [31]. Sequence logo analysis of KRC from γ- and δ-modules In the actinobacterial γ- and δ-modules, the stereochemical outcome of a KR is obscured by further dehydration catalyzed by DH. The dehydration mechanism by DH has

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• [32]. We sought to identify the heme binding site, but AlphaFold does not model this. However, this AlphaFold model was predicted to bind a heme cofactor by the consensus modeling tool COACH [33]. This protein–ligand model exhibited steric clashes with the heme and protein side chains (data not shown

• NnlA model in Figure 5A. Several of these residues are nearby the predicted heme binding site, which may suggest their importance in NNG binding near the heme. However, many of these residues are either far from the heme or would not orient NNG towards the distal pocket of the heme. Future mutagenesis

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• compounds (40, 43, 44, 47, 48, 50, 51, and 53–55) (Figure 7A). In addition, a structure-based mutagenesis study of SptF was performed to further amplify its catalytic potential. Firstly, the hydrophobic residues Ile63, Phe133, and Ile231, which compose the substrate binding site of SptF, were mutated. As a

• change their reaction products depending on the conformation of the terpenoid skeleton, the regiospecificity of the oxidation reaction can be modified by introducing random mutations in the substrate-binding site of αKG-dependent dioxygenase. The αKG-dependent dioxygenase AndA withdraws H-12 of

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• tweezers by the first equivalent generating an allosteric binding site specific to a second Hg2+ ion. While the addition of one equivalent of Hg2+ decreased the quantum yield to 0.09, the formation of a bis-coordinated [tweezers-Hg2]4+ complex resulted in a total luminescence quenching (quantum yield <10−3

• using metal complexes as switching units (Figure 20). This concept named “weak link approach” (WLA) [78] uses square planar d8-transition metal complexes with two hemilabile bidentate ligands composed of a strong binding site (phosphorus) and a weaker one (generally sulfur, oxygen, selenium, or nitrogen

• ) that is labile. By default, the complex is in a closed form with the functional units on each ligand facing each other due to the square planar geometry of the complex. By adding a first ancillary ligand (carbon monoxide, chloride,…) that strongly binds to the metal center, one weak binding site is

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• the GPR receptor can aggravate the symptoms of myeloid leukemia. In contrast to most GPR84 agonists which contain long alkyl chains, BIMs are not lipophilic molecules, which allow them to bind to the GPR receptor via an allosteric binding site and modulate GPR84’s rate of expression [2]. One

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• aligned the individual units of the tandem repeat CBM13 domains, indicated by the N-terminal (34-158) and C-terminal units (162-286) and compared those to the domains of ricin (Figure 1b). R-type lectins have a characteristic Q-x-W structural motif close to their binding site, which is highly conserved

• to elucidate the molecular mechanism that would enable the specific binding of C2-substituted galactose. The natural hypothesis here would be the creation of an additional pocket in the 3D structure of the binding site, accommodating the additional substituent at C2. However, as we observed little to

• (Val6 to Asp132) could be modelled, and unambiguous electron density permitted us to locate and model four cation binding sites (three in each structure) and one sugar binding site (Figure 4a,b and Figure S4, Supporting Information File 2). The complexed structures allowed us to shed light on the

Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions

• Julika Schlosser,
• Olga Fedorova,
• Yuri Fedorov and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 101–117, doi:10.3762/bjoc.20.11

• delivered without effect to the binding site, where the DNA-binding benzoquinolizinium ligand can then be generated as needed upon irradiation. Notably, the use of light for the activation of photo-controllable DNA ligands offers several advantages because it is easy to apply, traceless, and non-invasive

• within the binding site. The binding mode of the benzo[c]quinolizinium derivatives 3c,e–g with DNA was further examined with circular dichroism (CD) and linear dichroism (LD) spectroscopy (Figure 6 and Supporting Information File 1, Figures S12–S14). Hence, with increasing ligand-DNA ratio (LDR) weak

• binding angle α = 59° between the ligand 3f and the DNA helix, thus indicating a tilted orientation of the ligand relative to the DNA base pairs within the binding site. The DNA-binding ligands were also generated in situ in the presence of DNA. For that purpose, solutions of the styrylpyridines 2d–g and

Studying specificity in protein–glycosaminoglycan recognition with umbrella sampling

• Mateusz Marcisz,
• Sebastian Anila,
• Margrethe Gaardløs,
• Martin Zacharias and
• Sergey A. Samsonov

Beilstein J. Org. Chem. 2023, 19, 1933–1946, doi:10.3762/bjoc.19.144

• essential to explain their biological functions. In this study, the umbrella sampling (US) approach is used to pull away a GAG ligand from the binding site and then pull it back in. We analyze the binding interactions between GAGs of three types (heparin, desulfated heparan sulfate, and chondroitin sulfate

• /pdb, [37]). The third complex is known to exist in two different binding poses which are experimentally well established. In this study, the umbrella sampling (US) approach is used to pull away a GAG ligand from the binding site and then pull it back in. The main focus of our study is to evaluate

• RS-REMD (replica exchange with repulsive scaling), an MD-based docking method [41], to assure proper binding poses of the whole ligand and ring puckering and to be consistent with further simulations. The docked ligands cover the binding site the same way as ligands in the experimental structures

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• -capped calix[4]pyrrole cavitand 4. The heteroditopic receptor had multiple binding sites, proving efficient in encapsulating a CsF ion pair. The calix[4]arene-crown-6-capped pocket was exploited as an excellent binding site for the Cs+ cation, whereas the calix[4]pyrrole was aligned to trap the fluoride

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• ). The review of Lemaire et al., dedicated to the synthesis of glycerol ether, is complemental to this review article [57]. Of note, the review of Godfroid and Braquet attempted to decipher the binding site of PAF via a QSAR study [58]. 1.1 Synthesis of PAF and some building blocks The platelet

CO₂ complexation with cyclodextrins

• Cecilie Høgfeldt Jessen,
• Jesper Bendix,
• Theis Brock Nannestad,
• Heloisa Bordallo,
• Martin Jæger Pedersen,
• Christian Marcus Pedersen and
• Mikael Bols

Beilstein J. Org. Chem. 2023, 19, 1021–1027, doi:10.3762/bjoc.19.78

• change in spectrum of 7 provided 7 and CO2 compete for the binding site. To avoid problems with formation of hydrogencarbonate the experiments were conducted in a buffer at pH 3 where only a minor fraction of the carbonic acid (pKa1 = 3.6) is dissociated and since the hydration constant of CO2 is small

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• pocket of the enzyme. In contrast, the S2 pocket preferably accommodates amino acids having short aliphatic side-chains, but also recognizes aromatic amino acids, preferably phenylalanine. To study the structural requirements of the S1 binding site of the enzyme, we synthesized a series of ten dipeptide

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• , USA), to the two independent binding sites model. From the fit, the stoichiometry (n), binding enthalpy change (ΔH, kJ·mol−1), affinity constant (Ka, M−1), binding free energy change (ΔG, kJ·mol−1), and binding entropy change (ΔS, J·mol–1·K−1) for the first binding site were calculated. The

• thermodynamic parameters for the second binding site were not discussed but used to subtract the nonlinear residual heat at high molar ratios. Separate titration experiments of pure DMSO to the solution of tetracene in DMSO and DMSO to the solution of water in DMSO were carried out to account for potential

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

•  5) [21]. Gαi1 was selected as a positive control for subsequent studies because it can be expressed easily, has roughly 55% homology with the much more difficult to express Gαq [15], and chimeric proteins are available that have Gαi1 modified with a Gαq binding site for YM and FR [22]. R6A was

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• area above and below the central pore of the dimeric 14-3-3ζ protein is the most probable binding site for the ligand. Moreover, we predict that the position of the ligand is sensitive to the presence of phosphorylated C-Raf peptides. With a series of experiments, we confirmed the computational

• pairs of proteins (Figure 2b). Knowledge of the binding site is of critical importance for a potential bioanalytics application: if 1 would block one or both wells of the ω, it could prevent binding of ligand proteins, whereas a 1 binding site in the outer parts of the ω would not interfere with

• 1.5.2 [41]. To validate our method, we applied it to the QQJ-096/14-3-3/c-Raf complex for which the potential binding site was available from all-atom molecular dynamics simulations in a previous study [26]. Our results for this system are reported in the first part of the Supporting Information File 1