G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• . Remarkably, the ligands span a wide range of efficacies; in 10 cases, they act as agonists, in 11 as antagonist and twice as partial agonists. One key to this success is that the simulations were able to identify the most stable binding site of several alternatives in each case. Multiple binding sites We

• -adrenergic receptor [31], ligands can occupy more than one binding site along the binding path. In the case of vasopressin, a cyclic peptide hormone, the simulations revealed three different sites, the conventional orthosteric one that activates the ligand, an “intermediate” and a “vestibule” site

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• sphaeroides. With an increasing number of integrated recombinant enzymes balanced (over)expression gains importance in order to sustain optimal carbon flux in the production host from cultivation medium feed to the desired product. In this respect, determining the optimal strength of the ribosomal binding

• site (RBS) may be as crucial as the correct arrangement of the genetic elements on designed operons [85][86][87]. To this end, the lycopene reporter system represents a valuable tool in determining balanced expression of terpene centered heterologous pathways in E. coli [88][89]. Furthermore, a

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• site-directed inactivation of the NADPH-binding site. The tandem assay strategy was also used to try to identify residues potentially participating in the epimerization reaction [88]. This is an intriguing question, as comparative sequence analysis [57][90] fails to reveal any residues which are

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• functions as a binding site for the extension substrate, GPP or FPP. In contrast to FARM, the amino acid residues corresponding to SARM in ComQ are quite different from those in the typical FPP and GGPP synthases (Figure 4B). Since only the second aspartate is preserved in the corresponding region of ComQ

Spectral and DFT studies of anion bound organic receptors: Time dependent studies and logic gate applications

• Srikala Pangannaya,
• Neethu Padinchare Purayil,
• Shweta Dabhi,
• Venu Mankad,
• Prafulla K. Jha,
• Satyam Shinde and
• Darshak R. Trivedi

Beilstein J. Org. Chem. 2017, 13, 222–238, doi:10.3762/bjoc.13.25

• ][24][25][26]. The choice of the appropriate detection technique is highly essential as it directly dictates the efficacy of the sensor. Anion binding through colorimetric probes comprising of a binding site and a signaling unit works in a coordinative way yielding an optical output visible to the

• output, the signaling unit has been linked to a conjugated system possessing a hydroxy functionality which acts as binding site for anions. UV–vis, 1H NMR titration studies along with DFT studies of the receptors R1 and R2 would help to arrive at the binding mechanism. The presence of heteroatoms in the

• aromatic ring and possess hydrogen-bond donor functionality, namely a hydroxy group in the naphthyl part, which can act as an active binding site for anions. Additionally, both receptors R1 and R2 encompass an electron-withdrawing substituent, a CN group (R1) or a NO2 functionality (R2), in the para

Interactions between photoacidic 3-hydroxynaphtho[1,2-b]quinolizinium and cucurbit[7]uril: Influence on acidity in the ground and excited state

• Jonas Becher,
• Daria V. Berdnikova,
• Darinka Dzubiel,
• Heiko Ihmels and
• Phil M. Pithan

Beilstein J. Org. Chem. 2017, 13, 203–212, doi:10.3762/bjoc.13.23

• derivative 7 (Kb = 3 × 104 M−1) [36]. Although a comparison of binding constants from different studies has to be done carefully due to the different experimental conditions, it appears that linear acene-type quinolizinium derivatives fit better into the binding site of CB[7] with highly favorable energetic

• that can thread nicely into the binding site. Notably, the structurally resembling alkaloids berberine (8a) and palmatine (8b), that contain an angularly annelated quinolizinium unit, also bind to CB[7]. But whereas palmatine (8b) has essentially the same binding constant as 2 (Kb = 4.3 × 104 M−1, in

• increase of the pKa and pKa* values originates from the interaction of the acidic functionality with the carbonyl groups at the outer rim of the host molecule [34][55] and – as shown for cationic ligands – from the stabilization of the positive charge by the accommodation in the binding site [29

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

• -ethynylbenzamides 1 [35]. The rationale of our choice is based on molecular docking data. Using the published structure of the MDM2–p53 binding site, we have employed computational methods and focused library synthesis based on the isoindolinone template, to develop compounds with inhibitory activity. These studies

• docked into the MDM2 binding site. The docking protocol starts with the redocking of the MI63 analogue in the binding site to determine the lowest RMSD relative to the crystallographic pose. The ligand was successfully redocked with a RMSD of 0.59 Å. Determination of the single binding mode of spiro

• -isoxazolidin isoindolinone scaffold in the receptor/ligand complex was difficult because of the open and lipophilic nature of the p53 binding site on MDM2. Therefore, prediction of the possible binding mode was based on two energy types, i.e., the lowest binding energy of the largest cluster and the

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

• -based binding site identification servers is 3V [89]. Even though for some cases the largest pocket or cleft of a protein is its binding pocket, it is not necessarily true for all target proteins. Energy-based methods have been developed to address this issue and have shown more success than geometry

• phosphate probe which are used to identify the binding sites for drug-like molecules and phosphorylated ligands (such as ATP) respectively [92]. The best ligand binding site identified in HIV-1 protease by SiteHound is shown in Figure 4. This ligand binding site is the known inhibitor binding site in HIV-1

• reliable scoring functions are critical components of docking algorithms. Once a target protein structure is known and a potential drug binding site has been identified, small molecules that bind to this site need to be determined. In drug discovery, docking algorithms are used to find the best fit between

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• sweet-taste profile. In this context, Thordarson et al. studied the interaction of α-CD with thaumatin [93]. The 1D and 2D NMR experiments revealed that α-CD binds to aromatic residues of thaumatin with a binding constant of 8.5 M−1. As the active binding site of the thaumatin protein is known, the

• authors have synthesized a heptapeptide (Lys-Thr-Gly-Asp-Arg-Gly-Phe) that mimics this binding site of thaumatin. The results show that α-CD binds to the C-terminal solvent accessible phenylalanine residue with a binding constant of 8.8 M−1. As the α-CD may interact with the active binding site on

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• ) and the role of some amino acid residues of the catalytic site was characterized by the single-site mutagenesis [41]. It was suggested that the uracil binding site includes Gln166, the carboxamide group of which forms two strong hydrogen bonds 3N(H)···(O=)C(R)-NH2···(O=)C-2. Moreover, the carbonyl

Amidofluorene-appended lower rim 1,3-diconjugate of calix[4]arene: synthesis, characterization and highly selective sensor for Cu²⁺

• Rahman Hosseinzadeh,
• Mohammad Nemati,
• Reza Zadmard and
• Maryam Mohadjerani

Beilstein J. Org. Chem. 2016, 12, 1749–1757, doi:10.3762/bjoc.12.163

• (Hd, He) and –O–CH2 (Hf) porotons, which are close to the binding site of receptor L were affected and downfield shifted by the complexation of L with Cu2+. A detailed analysis of the 1H NMR spectra reveals the significant changes of almost all the other proton signals in the ligand. For instance, the

• peak of aromatic ring hydrogen atoms (Hc, resonated at 7.35 ppm) was converted to two distinct peaks at 7.20 and 6.95 ppm (Hc1, Hc2). In addition, signals belonging to the fluorene moieties and tert-butyl groups, which are quite far away from binding site, were also affected by complex formation. For

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• any cofactors, in spite of its flavin adenine dinucleotide (FAD) binding site [98][99]. The reaction mechanisms and biosynthetic enzymes involved in the rearrangement of versicolorin B (106) to demethylsterigmatocystin (107) have also been discussed controversely. Up to four genes (aflM, aflN, aflX

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

• hydrophilic pocket (Ser251 and Lys215) where the hydroxy groups of the sugar interact and a phosphonate binding site close to the magnesium ion located in the substrate binding site. Thus, as few cytosine-containing analogues were equipotent in terms of cN-II inhibition to their purine counterparts (Figure 1

• moderate inhibition (Figure 5) was observed for these derivatives indicating that they may not bind very tightly to the enzyme binding site. Nevertheless, five compounds 1i, 1h, 1n, 1o and 1q exhibited a more pronounced inhibition at 1 mM (Table 2) with at least 50% of inhibition. The nature, size and

• sticks) and 1q (green sticks) in the substrate binding site of cN-II. We then compared the three analogues bearing an aminophenyl substituent on the triazole ring with all possible orientations (ortho, meta or para) for the amino group (derivatives 1h, 1i and 1j). Interestingly, all of them showed very

Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions

• Golo Storch,
• Sebastian Pallmann,
• Frank Rominger and
• Oliver Trapp

Beilstein J. Org. Chem. 2016, 12, 1453–1458, doi:10.3762/bjoc.12.141

• paper, we describe the application of Doherty’s synthetic strategy for the synthesis of stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)” compounds bearing secondary amino groups for functionalization. The attachment of a 3,5-dichlorobenzoyl binding site is reported and non-covalent interactions as

• achiral auxiliaries or binding sites. In this study, we chose amide bond formation with 3,5-dichlorobenzoyl chloride (Figure 2B) in connection with our recent report [21] on non-covalent interaction properties of stereodynamic BIPHEP ligands with this binding site that is well known in HPLC stationary

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• docking score, it is plausible that compound 4 may bind LasR at the OdDHL binding site, and thus be capable of competitively disrupting OdDHL-dependent activation of LasR and thereby inhibiting pyocyanin production. Conclusion In conclusion, we have reported the discovery of 4, a potent inhibitor of

• . Binding poses of OdDHL and compound 4 in OdDHL binding site. Hydrogen bonds are shown in black dotted lines. a) Crystal structure of OdDHL bound to LasR LBD (PDB 2UV0 [31]). b) Top-scoring pose of compound 4 obtained by docking into LasR LBD. Unexpected synthesis of compound 4. The synthesis of 2 was

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

• composition can be varied. Bifunctional linkers for conjugation of oligonucleotides and polyamides using CuACC. The target duplex contains a 29 base pair fragment from HIV proviral DNA [35] and a T4 hairpin is connecting two strands: a 16 base pair polypurine-polypyrimidine tract (TFO-binding site – is

• indicated by a red rectangle), an adjacent overlapping poly(dA:dT) tract (MGB-binding site – by a blue rectangle). Fluo is a fluorescein label. A) Sequence derived from the murine pericentromere repeat fragment with only one target site for the polyamide F1-NH2 [2][3]. The target sequence is underlined. B

Artificial Diels–Alderase based on the transmembrane protein FhuA

• Hassan Osseili,
• Daniel F. Sauer,
• Klaus Beckerle,
• Marcus Arlt,
• Tomoki Himiyama,
• Tino Polen,
• Akira Onoda,
• Ulrich Schwaneberg,
• Takashi Hayashi and
• Jun Okuda

Beilstein J. Org. Chem. 2016, 12, 1314–1321, doi:10.3762/bjoc.12.124

• –Alderases reported so far used soluble proteins, where the binding site of Cu(II) was formed either by site-directed mutagenesis [22][23], by incorporation of a suitable ligand, or copper complex in an apo-protein [24][25][26][27]. Here we report on the use of the robust transmembrane protein Ferric

A modular approach to neutral P,N-ligands: synthesis and coordination chemistry

• Vladislav Vasilenko,
• Torsten Roth,
• Clemens K. Blasius,
• Sebastian N. Intorp,
• Hubert Wadepohl and
• Lutz H. Gade

Beilstein J. Org. Chem. 2016, 12, 846–853, doi:10.3762/bjoc.12.83

• neutral κ2-P,N-ligands comprising an imine and a phosphine binding site. These ligands were reacted with rhodium, iridium and palladium metal precursors and the structures of the resulting complexes were elucidated by means of X-ray crystallography. We observed that subtle changes of the ligand backbone

• hydrogenations [1][2] and allylic substitutions [3][4] to Heck reactions [5] and conjugate additions to enones [6]. Their popularity arises from the inherent electronic disparity of the phosphorus and the nitrogen donor groups, rendering one binding site a soft π-acceptor featuring a pronounced trans effect and

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• between F288 and glutamic acid 287 (E287) with the peptide motif arginine-tryptophan-x-x-tryptophan (RWxxW, x represents an arbitrary amino acid) was found. Mutants F288L and E287A showed reduced or no detectable enzyme inhibition, thus indicating a secondary binding site for potential MraY inhibitors

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

• zinc complexes (Figure 3) as mimics of the enzyme Carbonic Anhydrase. The ligands for these complexes are notoriously difficult to work with chromatographically, but I managed to synthesize a few derivatives that not only replicated the zinc binding site, but also some of the functionality that

• competition gives the computationalists a unique opportunity to try and hone their skills, which in return provides feedback to those interested in the a priori prediction of the thermodynamics of binding. For example, being able to predict ahead of time which ligands binds best to a protein binding-site has

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

• , the remaining pharmacophore part fits perfectly into the binding site. What makes the difference in the relative binding energies between those two compounds seems to be the steric repulsion exerted by the methyl group of 6. This repulsion causes a twisting of the G2540 nucleobase and hence the

• importance for the overall binding process: in fact, if G2540 is interacting with the morpholine ring, the drug is “clamped” in the binding site, because its side chain is stabilized by stacking interactions. While our model recognize different enantiomers (guest 13 and 16 are stabilized in comparison with

• destabilized by nearly 70 kJ/mol in comparison with the guest 20. The increased steric effect is once again rising the energy of the complex and pushing the ligand outside the binding site. Conclusion The proposed combination of computational power and chemical intuition led to the prediction of several new

Learning from the unexpected in life and DNA self-assembly

• Jennifer M. Heemstra

Beilstein J. Org. Chem. 2015, 11, 2713–2720, doi:10.3762/bjoc.11.292

• be a privileged structure for the engineering of aptamers into split aptamers, as it offers two putative splitting sites that are distant from the typical target binding site (Figure 4a). Excitingly, Stojanovic and co-workers had recently demonstrated that SELEX could be carried out using a

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) – precursors for dyes and drugs

• Enas M. Malik,
• Younis Baqi and
• Christa E. Müller

Beilstein J. Org. Chem. 2015, 11, 2326–2333, doi:10.3762/bjoc.11.253

• potential as drug targets. In this context, a library of AQ derivatives, structurally related to RB-2, has been synthesized and evaluated at a variety of purinergic targets; all of which are characterized by a nucleotide binding site [28][42][43][44][45][46][47][48]. The nature of the substituent at

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

• aromatic moiety with the so-called tyrosine gate at the entrance of the carbohydrate binding site, formed by Y48 and Y137. Additional interactions exerted by extended aglycone portions can further improve ligand affinity for FimH; for example ortho-chloro substitution of the phenyl ring (compounds 2 and 5

• consideration of Amadori products 9 and 10 as FimH ligands The complexation of MeMan (1, cf. Figure 1) as the most simple FimH ligand in the carbohydrate binding site of FimH has been described in detail [10]. It is depicted in a simplified cartoon fashion in Figure 2. The α-configured aglycone moiety (OCH3 in

• green) of the glycoside is pointing out of the binding site, whereas the axial 2-OH group as well as all other hydroxy groups of the sugar ring are complexed within the FimH carbohydrate binding site. Complexation of mannoside ligands is further supported by a conserved water molecule inside the

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

• . In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3–2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 µM, forming complexes with low stoichiometry, and no

• energy of binding from the enthalpic and entropic contributions. In addition, the method can be used to determine the stoichiometry of the formed protein–ligand complex indicating the ratio of peptide ligand molecules relative to each protein binding site thereby giving valuable insights into the

• , soluble complexes with a stoichiometry of <2 peptide ligands per protein binding site, while pHPMA and hPG formed colloidal suspensions/dispersions with stoichiometries >2 ligands per binding site. Molecular dynamics calculations suggested that conjugates with multivalently presented peptides on dextran