New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• chloride to various primary and secondary amines. The authors propose that L1 binding with chloride results in a more electrophilic tritylated DMAP cation, and the binding affinity of the catalyst was found to correlate with the N-alkylation rate. Following the aforementioned studies, the Mancheno group

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• coordinates of the complex of the MI63-analogue with MDM2 [53][54]. The protein structure PDB ID 3LBL was chosen as the reference receptor because its ligand had high binding affinity and high resolution (1.6 Å). Docking studies were performed using AutoDock4.2 and both enantiomers of compounds 6a–f were

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• specific biological information as well. The BIND database contains protein complex information and biomolecular interactions [85]. BindingDB contains measured binding affinity information of proteins that are considered to be targets for drugs [86]. This database contains over one million binding data

• docking In molecular docking, how well a drug binds to its target is determined by the binding affinity prediction of the pose. This is done by scoring. Scoring is used to evaluate and rank the target–ligand complexes predicted by docking algorithms. Scoring functions are used in SBDD for scoring and

• scoring functions use evaluation criteria such as binding pose, binding affinity and ranking of true binders [114]. Wang et al. evaluated the performance of fourteen different scoring functions using 800 protein–ligand complexes in the PDBbind database [113]. The performance was evaluated by the predicted

A self-assembled cyclodextrin nanocarrier for photoreactive squaraine

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2016, 12, 2535–2542, doi:10.3762/bjoc.12.248

• squaraines can also be immobilized onto CDVs. For this purpose, the squaraines are equipped with two adamantane functions that bind into the cavities of cyclodextrin on the surface of the CDVs (Figure 1). The resulting divalent host–guest interaction should lead to a higher binding affinity of the squaraine

Robust C–C bonded porous networks with chemically designed functionalities for improved CO₂ capture from flue gas

• Damien Thirion,
• Joo S. Lee,
• Ercan Özdemir and
• Cafer T. Yavuz

Beilstein J. Org. Chem. 2016, 12, 2274–2279, doi:10.3762/bjoc.12.220

• pressure of CO2 in flue gas emission) and 273 K, the uptake is slightly higher than the starting COP-156. The chemisorptive behavior and stronger binding affinity is reflected in the higher Qst value of 49.9 kJ mol−1. The moderate binding energy is optimal for CO2 capture, as too strong binding requires

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• binding affinity and not the activity. Nevertheless, we focused on the most active compounds and determined the main interactions with the target protein that will be required for lead optimization. We first analysed compounds with the smallest substituent on the triazole nucleobase (derivatives 1n–q). As

Application of Cu(I)-catalyzed azide–alkyne cycloaddition for the design and synthesis of sequence specific probes targeting double-stranded DNA

• Svetlana V. Vasilyeva,
• Vyacheslav V. Filichev and
• Alexandre S. Boutorine

Beilstein J. Org. Chem. 2016, 12, 1348–1360, doi:10.3762/bjoc.12.128

• helices by TFO-MGB conjugates was evaluated by gel-shift experiments. The presence of MGB in these conjugates did not affect the binding parameters (affinity and triplex stability) of the parent TFOs. Keywords: binding affinity; click chemistry; Cu(I)-catalyzed azide–alkyne cycloaddition; pyrrole

Creating molecular macrocycles for anion recognition

• Amar H. Flood

Beilstein J. Org. Chem. 2016, 12, 611–627, doi:10.3762/bjoc.12.60

• triazolophane’s rigidity and that preorganization may be crucial for the large binding affinity. To test this idea, we examined the macrocyclic effect using an oligomer (Figure 8a) that folds up around chloride [17]. The affinity decreased by four orders of magnitude to ≈100 M−1, perfectly consistent with

• upon the correct estimate of the binding affinity. We originally missed a few features that impacted the accuracy of the binding constants. While these issues are quite common, their impact can be huge: our affinities had to be modified twice from Ka = 130,000 M−1 to 11,000,000 M−1 to 4,700,000 M−1 [6

• /acetonitrile). The aryl-triazole foldamer 24 formed a double helix with overall stability of β2 = 1012 M−2 [48]. Importantly, while we observed clear penalties to the binding affinity when we added extra water, we also saw that extra water increases the stability of the duplex. The analogy to hydrophobic

Copper-mediated arylation with arylboronic acids: Facile and modular synthesis of triarylmethanes

• H. Surya Prakash Rao and
• A. Veera Bhadra Rao

Beilstein J. Org. Chem. 2016, 12, 496–504, doi:10.3762/bjoc.12.49

• binding affinity [21], inhibition of hepatic cholesterol [22], inhibition of aldose reductase [23], antiproliferative [24], antiviral, cytotoxic [25], antifungal [26], anti-HIV [27][28][29] and antibacterial activity [30]. Although rare, there are a few natural products, for example, melanervin (5), a

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• group and the morpholine nitrogen. Though not observable in the solid state, this movement increases the binding affinity of linezolid under biological conditions. Due to our simulation this low energy minimum is populated 83% of the time at 310 K, dominating the recognition process. We repeated our

• contains a NH2 group that is able to form a weak H-bond, its amidic character and the lack of a chiral center leads to a side chain orientation parallel to the 1,2,4-oxadiazole ring, changing the overall binding mode in comparison with linezolid, and by this decreasing the overall binding affinity. Our

• the acetamidic arm and the G2540 phosphate group. Table 2 summarizes the results for the calculated relative binding energies. Due to our simulation, three among the 20 new linezolid analogues show a higher binding affinity in comparison with linezolid, which is not too bad for a first hit rate. In

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• interested in bisintercalators and the question of rigid vs flexible linkers? The triaminotriazine unit was designed to provide selective recognition of U–U or T–T mismatches, but on its own was viewed as unlikely to provide significant binding affinity because the hydrogen bonding simply involves replacing

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

• Camilla Matassini,
• Stefania Mirabella,
• Andrea Goti,
• Inmaculada Robina,
• Antonio J. Moreno-Vargas and
• Francesca Cardona

Beilstein J. Org. Chem. 2015, 11, 2631–2640, doi:10.3762/bjoc.11.282

• nonavalent (86%) one. For this latter compound (11·HCl), IC50 = 179 μM was calculated [36]. This outcome is particularly desirable with multimeric iminosugars for increasing the overall binding affinity of weak inhibitors, as recently pointed out by Winum and Ulrich in a recent review [37]. It should also be

Size-controlled and redox-responsive supramolecular nanoparticles

• Raquel Mejia-Ariza,
• Gavin A. Kronig and
• Jurriaan Huskens

Beilstein J. Org. Chem. 2015, 11, 2388–2399, doi:10.3762/bjoc.11.260

• binding affinity. The positively charged Fc8-PAMAM multivalent guest was prepared according to a procedure developed in our group [27]. The positively charged Ad-terminated PAMAM (Ad8-PAMAM), used as a control, was prepared according to a literature procedure [11]. The neutral Fc-PEG stabilizer was

• of Ad is efficiently blocked by CD, which is in line with the approx. 30 times higher binding affinity of Ad (see above). Most importantly, this graph (Figure 5) confirms a 1:1 binding stoichiometry of the system. These results demonstrate that SNPs form optimally at a 1:1 stoichiometry at which all

• host–guest ratio at 1:1 and a high ionic strength of 0.2 M NaCl. Two different parameters were considered to study the effect of a stopper: length and binding affinity. The formation of SNPs was studied using constant concentrations of [CD] = 100 µM (CD is the number of moieties from CD-PEI) and [Fc

Co-solvation effect on the binding mode of the α-mangostin/β-cyclodextrin inclusion complex

• Chompoonut Rungnim,
• Sarunya Phunpee,
• Manaschai Kunaseth,
• Supawadee Namuangruk,
• Kanin Rungsardthong,
• Thanyada Rungrotmongkol and
• Uracha Ruktanonchai

Beilstein J. Org. Chem. 2015, 11, 2306–2317, doi:10.3762/bjoc.11.251

• -solvent enhances the solubility of α-MGS with some effects on the binding affinity with β-CD, depending on the concentration employed. Keywords: α-mangostin; β-cyclodextrin; binary complex; inclusion complex; Introduction Solubilization of otherwise poorly soluble drugs under physiological conditions to

• additive contributions has potential to provide relationship between structure and binding affinity as well as the solvation effects. Theoretical basis of solvation free energy decomposition and the Free Energy Perturbation (FEP) formalism allowing additive for free-energy contributions arising from

• inclusion complex, as seen by a reduction in ΔGsolv at high ethanol percentages. In contrast, the entropies of all systems were likely similar (−T∆S of ≈13 kcal/mol). After combining the interaction energy (1), solvation (2) and entropy (3) terms, the binding affinity of the α-MGS/β-CD complexation at 0–60

Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

• Keiichi Motoyama,
• Yumi Hirai,
• Rena Nishiyama,
• Yuki Maeda,
• Taishi Higashi,
• Yoichi Ishitsuka,
• Yuki Kondo,
• Tetsumi Irie,
• Takumi Era and
• Hidetoshi Arima

Beilstein J. Org. Chem. 2015, 11, 2079–2086, doi:10.3762/bjoc.11.224

• levels in NPC1 fibroblasts, indicating the improvement of impaired autophagy by HP-β-CyD [28]. Therefore, it is necessary to investigate whether Lac-β-CyD can improve an autophagy function in NPC-like cells. Galactose density is one of the critical parameters of affinity to ASGPR. The binding affinity of

Supramolecular chemistry: from aromatic foldamers to solution-phase supramolecular organic frameworks

• Zhan-Ting Li

Beilstein J. Org. Chem. 2015, 11, 2057–2071, doi:10.3762/bjoc.11.222

• approximately 1.8 nm in diameter [69]. At first we expected that this series of triazole foldamers would be good hydrogen bonding acceptors. Intriguingly, the foldamers did not exhibit observable binding affinity to saccharides or amide derivatives even in less polar chloroform. Liyan designed different

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• cyclized product. The cleavage of the acetate groups with sodium methoxide in methanol gave the glycophane (a glycophane is a hybrid of carbohydrate and cyclophane) 143 (27%, Scheme 21). The synthesis of fullerene-related molecules with high binding affinity and/or high selectivity is an active research

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• disclosed a study detailing the flow synthesis of a library of GABAA agonists which was linked to in-line frontal affinity chromatography (FAC) in order to directly generate binding affinity data for these new entities towards human serum albumin (HSA), a highly abundant protein in human blood plasma [110

• system. After establishing the void volume of this column, two different literature known marker compounds (diclofenac sodium and isoniazid) were used in order to calibrate the system based on their retention time which could be directly correlated to the protein binding affinity. Furthermore, as the

• µL, 67.5 µM) were passed through the binding assay column allowing quick determinations of their HSA binding affinity. This proof of concept study therefore marks one of the first published reports where flow chemical synthesis is combined with direct biological evaluation of new structures thus

Azobenzene-based inhibitors of human carbonic anhydrase II

• Leander Simon Runtsch,
• David Michael Barber,
• Peter Mayer,
• Michael Groll,
• Dirk Trauner and
• Johannes Broichhagen

Beilstein J. Org. Chem. 2015, 11, 1129–1135, doi:10.3762/bjoc.11.127

• of these findings into account, we conclude that the sulfonamide–zinc interaction dominates the binding affinity. The electronic differences of our azobenzene library is expressed by their absorption spectra (as an indicator for the electron richness of the azobenzene) or in their Hammett constants

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• ) scoring function and correlated with the binding affinity of the ligand for the FimH CRD. More negative scores indicate higher binding affinity than less negative values (Table 1). According to this docking procedure, Amadori products 9 and 10 have similar scores, which lie in the range of that for MeMan

Glycoluril–tetrathiafulvalene molecular clips: on the influence of electronic and spatial properties for binding neutral accepting guests

• Yoann Cotelle,
• Marie Hardouin-Lerouge,
• Stéphanie Legoupy,
• Olivier Alévêque,
• Eric Levillain and
• Piétrick Hudhomme

Beilstein J. Org. Chem. 2015, 11, 1023–1036, doi:10.3762/bjoc.11.115

• intramolecular distance between TTF sidewalls and the strongest π-donor ability. Interaction with tetrafluoroquinodimethane (F4-TCNQ) The binding affinity of molecular clip 3 (5 × 10−4 M in CH2Cl2) was studied by a UV–visible titration with the electron acceptor F4-TCNQ (10−5 M in CH2Cl2). Addition of aliquots

Multivalency as a chemical organization and action principle

• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 848–849, doi:10.3762/bjoc.11.94

• supramolecular designer systems [4][5]. The influence of spacer length and flexibility on the binding affinity of ligands [6] will be examined as well as the mechanical stability of complexes [7]. Furthermore, the Thematic Series covers the synthesis of various new glycoarchitectures for multivalent interactions

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a KD > 1 mM

• sequences contained in numerous proteins including the core splicing protein SmB/B´and several splicing factors including splicing factor 3B4 (SF3B4) [16][17]. Recently, the enhanced binding affinity of bivalent and tetravalent peptide ligands to this protein was described suggesting that multivalent

• multivalent peptide–polymer conjugate to the tandem WW domain Binding studies with peptide–polymer conjugates were conducted employing isothermal titration calorimetry (ITC). This method enables the determination of the binding affinity of the multivalent ligands and elucidates the composition of the free

Influence of length and flexibility of spacers on the binding affinity of divalent ligands

• Susanne Liese and
• Roland R. Netz

Beilstein J. Org. Chem. 2015, 11, 804–816, doi:10.3762/bjoc.11.90

• binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50

• range as the size of a receptor binding pocket. Keywords: binding affinity; divalent ligand; effective concentration; multivalency; Introduction Multivalency is a common design principle in biological systems. The simultaneous binding of several, relatively weakly binding partners is a widely used

• strategy to strengthen the overall binding affinity [1][2][3]. Multivalency is believed to play an important role in evolutionary processes, since the collective interaction of several rather simple ligands makes the development of more complex binding partners with a higher binding affinity unnecessary [2

Impact of multivalent charge presentation on peptide–nanoparticle aggregation

• Daniel Schöne,
• Boris Schade,
• Christoph Böttcher and
• Beate Koksch

Beilstein J. Org. Chem. 2015, 11, 792–803, doi:10.3762/bjoc.11.89

• binding constants, as, for example, R2A2 shows the highest binding affinity, produces the greatest release of energy and has the smallest binding energy. With increasing peptide length, the binding affinity decreases, as does the release of energy, which is indicated by the increase in molar binding