Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• of PpyS, docking studies of the substrates onto the catalytic cysteine were performed. The resulting model suggested that a glutamate residue, which reaches into the catalytic cavity of the respectively other homodimer, acts as a base by forming a hydrogen bond with the α-carbon of the covalently

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

• aureus), VRE and Hi (Haemophilus influenzae) bacterial strains, it is currently undergoing clinical trials. An earlier docking study of 7 by Shaw et al. [47] postulated an increased potency mediated by additional interactions between the ribosomal active site and the pyridine and tetrazole rings from 7

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• proceed without becoming “trapped” in an intermediate energy well. For some conformers of the bisabolyl cation, many trajectories proceeded to the cedryl cation without significant delay in the regions of the homobisabolyl and acorenyl cations. Subsequent automated docking calculations of carbocations

Determination of formation constants and structural characterization of cyclodextrin inclusion complexes with two phenolic isomers: carvacrol and thymol

• Miriana Kfoury,
• David Landy,
• Steven Ruellan,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2016, 12, 29–42, doi:10.3762/bjoc.12.5

• conformations was carried out by a conformational Monte Carlo research method using the MMFFs force field in the presence of water (GB/SA implicit model) with the generation of 5000 conformations (FMNR conjugate gradient minimization convergence fixed to 0.01 kJ Å−1 mol−1). Prior to docking and simulations, the

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• covalent binding of the fatty acid precursor, as well as amino acids present at the dimer interface (Figure S3, Supporting Information File 1). Using this model we performed docking studies by covalently docking 14 and 16 (Figure 2) into the active site C129, revealing that the binding cavity of modeled

• , Supporting Information File 1) and docking experiments (Figure S9, Supporting Information File 1) with the proposed substrate 17 and intermediate 19 to the active site C124 also confirmed the glutamic acid inside the binding pocket as catalytically important suggesting a biosynthesis model (Scheme S1

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

• E. coli bacteria by means of molecular docking and bacterial adhesion studies. It turns out that Amadori rearrangement products have a limited activity as inhibitors of bacterial adhesion because the β-C-glycosidically linked aglycone considerably hampers complexation within the carbohydrate binding

• site of the type 1-fimbrial lectin FimH. Keywords: Amadori rearrangement; bacterial adhesion; C-mannosides; docking studies; FimH ligands; Introduction The Amadori rearrangement (AR) is the reaction in which aldohexoses react with suitable amines under acidic catalysis to 1-amino-1-deoxyketohexoses

• the FimH CRD might be possible and that Amadori products could indeed function as antagonists of natural FimH. Docking of Amadori products 9 and 10 into the carbohydrate binding site of FimH In order to visualise the complexation of Amadori rearrangement products 9 and 10, respectively, inside the

Discrete multiporphyrin pseudorotaxane assemblies from di- and tetravalent porphyrin building blocks

• Mirko Lohse,
• Larissa K. S. von Krbek,
• Sebastian Radunz,
• Suresh Moorthy,
• Christoph A. Schalley and
• Stefan Hecht

Beilstein J. Org. Chem. 2015, 11, 748–762, doi:10.3762/bjoc.11.85

• significant attention mediated in particular by the desire to understand biological phenomena, such as virus docking to cells [27], toxin inhibition [28], or leucocyte recruitment in inflammation processes of the endothelium [29]. Multivalency has also inspired synthetic supramolecular architecture as it not

Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

• Bodee Nutho,
• Wasinee Khuntawee,
• Chompoonut Rungnim,
• Piamsook Pongsawasdi,
• Peter Wolschann,
• Alfred Karpfen,
• Nawee Kungwan and
• Thanyada Rungrotmongkol

Beilstein J. Org. Chem. 2014, 10, 2789–2799, doi:10.3762/bjoc.10.296

• to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular

• docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less

• understand the two flavonoids/β-CD complexes, hesperetin and naringenin complexes, in aqueous solution. The PM3 method was applied to calculate the energy regarding the antioxidant property of the flavonoid chysin in the complex with β-CD [32]. Interestingly, the molecular docking study on the fisetin/β-CD

Effect of cyclodextrin complexation on phenylpropanoids’ solubility and antioxidant activity

• Miriana Kfoury,
• David Landy,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2014, 10, 2322–2331, doi:10.3762/bjoc.10.241

• most probable conformation of the β-CD/PP complexes and to give a meaningful 3D visualization of the complexes. Two docking strategies were used: i) inclusion into the CD cavity through the propenyl or allyl side chain of PP and ii) inclusion through the hydroxy or methoxy group. In both cases guests

• are allowed to penetrate the cavity through the wider rim of the CD. The computed complexation energies (ΔE) were calculated upon the docking of each PP into the β-CD cavity. The energy variation (ΔE) was used to find the most stable configurations of the inclusion complexes. The most stable

• conformations obtained from the two docking strategies and the corresponding energies (ΔE) are shown in Figure 4 in the case of 1 (see Supporting Information File 1, Table S1 for other compounds). No preferential inclusion mode was observed, the result being in agreement with previous NMR results [23

Multivalent scaffolds induce galectin-3 aggregation into nanoparticles

• Candace K. Goodman,
• Mark L. Wolfenden,
• Pratima Nangia-Makker,
• Anna K. Michel,
• Avraham Raz and
• Mary J. Cloninger

Beilstein J. Org. Chem. 2014, 10, 1570–1577, doi:10.3762/bjoc.10.162

• as a cellular docking site or a crosslinker for microorganisms binding to pathogens directly [20][21], and galectin-3 can act as a scaffold for the presentation of ligands such as lipopolysaccharides into an aggregate that stimulates cellular responses [19]. Binding affinities have been reported for

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

• Thomas A. Munro,
• Wei Xu,
• Douglas M. Ho,
• Lee-Yuan Liu-Chen and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• attachment point and linker for this second moiety would also be required. Docking 1 to an early rhodopsin-based homology model of κ-OR, Kane proposed a binding pose qualitatively similar to that of the HPP moiety of JDTic, placing the furan ring near Tyr3207.43 [8][18]. Indeed, at the time we commenced our

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• natural product. Based on the information [48][49] that balanol binds to the ATP-docking site of protein kinase, all the three distinct domains present in the natural product such as the benzophenone core [50][51][52], the azepine core [53][54][55][56][57][58][59] and the p-hydroxybenzamide [60][61] unit

Space filling of β-cyclodextrin and β-cyclodextrin derivatives by volatile hydrophobic guests

• Sophie Fourmentin,
• Anca Ciobanu,
• David Landy and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1185–1191, doi:10.3762/bjoc.9.133

• contributor to the driving force of complex formation [15]. The accumulation of basic understanding is essential for the formulation of precise docking programs, which estimate and screen the binding of drug candidates for biological receptors [16][17]. Practical applications of native β-CD, such as drug

• by means of docking simulations. Measured binding free energies were plotted as a function of the simulated inclusion enthalpies (Figure 6), defined as the enthalpy differences between the inclusion compounds and the free species. A significant linear correlation was obtained, confirming that the

• simulations. The docking of each guest inside host 4 was realized by means of Monte Carlo searches, with the generation of 5000 conformations (Polak–Ribiere conjugate gradient minimization, convergence fixed to 0.05 kJ Å−1 mol−1). During the search, host 4 was kept rigid, while the guest was freely modified

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• compounds performed poorly, binding with higher affinity to blood proteins than to SOD1, suggesting that these compounds may have significant off-target activity [37]. Docking calculations were performed to model the inhibitors at the dimer interface and a database of small molecules was screened to

• identify molecules that satisfied the docking constraints [37]. Twenty new compounds were identified and analyzed for inhibition of SOD1 A4V aggregation as well as binding to SOD1 in the presence of human plasma. Six of these compounds (Figure 7) tested positively in these assays [37], indicating that they

Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes

• Tony Taldone,
• Anna Rodina,
• Erica M. DaGama Gomes,
• Matthew Riolo,
• Hardik J. Patel,
• Raul Alonso-Sabadell,
• Danuta Zatorska,
• Maulik R. Patel,
• Sarah Kishinevsky and
• Gabriela Chiosis

Beilstein J. Org. Chem. 2013, 9, 544–556, doi:10.3762/bjoc.9.60

• [19], extensive SAR [20][21], and docking experiments [9], the N9-position of the purine scaffold was shown to be an ideal site for attachment since it is directed towards the solvent. Furthermore, the amino group of 1a or the desisopropyl analogue 1b provided a convenient handle with which to attach

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

• Vijayanand Chandrasekaran,
• Katharina Kolbe,
• Femke Beiroth and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2013, 9, 223–233, doi:10.3762/bjoc.9.26

• that of the standard inhibitor methyl mannoside. These findings could be rationalised on the basis of computer-aided docking studies. The properties of the new azobenzene mannobioside have qualified this glycoside to be eventually employed on solid support, in order to fabricate photoswitchable

• photochromic properties, and testing of mannobioside 2 as an inhibitor of type 1 fimbriae-mediated bacterial adhesion. Interpretation of the test results was supported by computer-aided docking studies. Results Synthesis of azobenzene mannobioside 2 For the preparation of azobenzene mannobioside 2, the

• computer-aided docking studies to get an idea of their interactions with the carbohydrate-recognition domain (CRD) of the lectin. Docking of azobenzene mannobioside 2 into the carbohydrate binding site of FimH To visualise complexation of the (E)- and (Z)-isomers of azobenzene mannobioside 2 within the CRD

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• -based probe derived from 1 was used to identify mammalian cathepsin B as a potentially important off-target of 1 and 4. Computational docking studies and the evaluation of truncated analogues of 4 reveal structural determinants for TcCYP51 binding, information that will be useful in further optimization

• hypothesis that the 4-pyridyl ring in 4 is involved in binding TcCYP51. The 2-pyridyl ring system in 3 is presumably unable to chelate heme in TcCYP51 due to steric hindrance from the immediately adjacent amide linkage. Computational docking studies We next employed computational docking and a model derived

• from the crystal structure of TcCYP51 to compare predicted binding modes of 4 and (R)-5. The two ligands were docked by using the induced-fit docking protocol with Glide XP [34], and the models were further refined by minimizing the energies of the ligand and surrounding residues (within 5 Å of ligand

Synthesis and in silico screening of a library of β-carboline-containing compounds

• Kay M. Brummond,
• John R. Goodell,
• Matthew G. LaPorte,
• Lirong Wang and
• Xiang-Qun Xie

Beilstein J. Org. Chem. 2012, 8, 1048–1058, doi:10.3762/bjoc.8.117

• them are in accordance with Lipinski’s rules. Virtual docking and ligand-based target evaluations were performed for the β-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the

• (PDB) and ChEMBL, it is possible to map new compounds into existing chemical space and to predict protein targets for new compounds, for which there are two complementary strategies that can be implemented. One is a structure-based docking strategy, in which a query compound is fit into a series of

• predict potential targets of the newly synthesized library of β-carboline-containing compounds. High-throughput docking studies for protein-target prediction of newly synthesized compounds Molecular docking studies were performed with the 34 newly synthesized compounds, represented by scaffolds 1, 2, 3

The use of glycoinformatics in glycochemistry

• Thomas Lütteke

Beilstein J. Org. Chem. 2012, 8, 915–929, doi:10.3762/bjoc.8.104

• CHARMM [97] input files from PDB files that contain carbohydrates. Various tools to predict the occupancy state of potential glycosylation sites from protein sequence data are available as well (Table 5). If a protein–carbohydrate complex is to be modeled, generally available docking tools such as

• AutoDock [113] can be used to identify the binding position. These tools, however, often do not sufficiently consider the peculiarities of protein–carbohydrate complexes, such as CH–π interactions [13]. Therefore, BALLDock/SLICK has been developed specifically for protein–carbohydrate docking [92][93]. One

• of the major problems of docking algorithms in general is the identification of the correct conformation among the potential binding modes [100]. Therefore, computational docking approaches are frequently combined with wet-lab experiments, such as saturation transfer difference NMR (STD NMR) or

An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells

• Grazia Marano,
• Claas Gronewold,
• Martin Frank,
• Anette Merling,
• Christian Kliem,
• Sandra Sauer,
• Manfred Wiessler,
• Eva Frei and
• Reinhard Schwartz-Albiez

Beilstein J. Org. Chem. 2012, 8, 787–803, doi:10.3762/bjoc.8.89

• , revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site. These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis

• (hydroxymethyl)furan and benzoylated galactose imidate, is nontoxic and antagonizes cell physiological processes in vitro that are important for the dissemination and growth of tumor cells in vivo. Keywords: angiogenesis; biomimetic synthesis; carbohydrates; in silico blind docking; melanoma cells

• interaction of GSF with integrins. To find possible binding sites for GSF, we used a “blind docking” approach to screen the protein surface of the extracellular domain of αvβ3, the crystal structure of which was published by Xiong et al. [26]. In an initial validation study, we performed multiple blind

Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

• Janja Makarević,
• Milan Jokić,
• Leo Frkanec,
• Vesna Čaplar,
• Nataša Šijaković Vujičić and
• Mladen Žinić

Beilstein J. Org. Chem. 2010, 6, 945–959, doi:10.3762/bjoc.6.106

• close to trans-coplanar positioning of NH and Cα-H protons in both groups The low energy conformations of (S,R)-1b and (S,S)-1b were used for docking calculations to generate the hydrogen bonded dimers of extended gelator molecules involving both, the oxalamide and Leu-NH protons (Supporting Information

En route to photoaffinity labeling of the bacterial lectin FimH

• Thisbe K. Lindhorst,
• Michaela Märten,
• Andreas Fuchs and
• Stefan D. Knight

Beilstein J. Org. Chem. 2010, 6, 810–822, doi:10.3762/bjoc.6.91

• photoactive mannosides 1, 2, 3, and 5, we have performed computer-aided docking studies using FlexX [17][18][19] to get an idea about their binding to the bacterial lectin FimH, as reported earlier [20]. FlexX produces so-called scoring values for each docked ligand, which can be regarded as a rough estimate

• of its free binding energy. Low (more negative) scores correlate with high affinities, whilst higher scores reflect diminished binding potency (Table 1). Docking was based on two different X-ray structures. In the first case, crystals with an open tyrosine gate were taken as the basis [7], whilst in

• 5. Consequently, the synthetic photoactive mannosides are suited as ligands for the bacterial lectin FimH. Comparison of the measured IC50-values with the theoretical docking results, discloses a somewhat limited value of the computer-aided predictions in this case. Docking suggested that mannosides

A bivalent glycopeptide to target two putative carbohydrate binding sites on FimH

• Thisbe K. Lindhorst,
• Kathrin Bruegge,
• Andreas Fuchs and
• Oliver Sperling

Beilstein J. Org. Chem. 2010, 6, 801–809, doi:10.3762/bjoc.6.90

• lectin domain was probed by computational docking studies [16]. Three new potential carbohydrate binding cavities on the surface of the FimH lectin domain, in addition to the mannose pocket at the tip of the domain, were identified which have a marked preference for the same subset of high-mannose

• the known CRD at the tip of FimH and the suggested second binding site, which is a more extended region on the protein (Figure 1). Docking using FlexX [22][23][24] recommended a spacer of 10 to 15 amino acids to ligate the two different carbohydrate ligand portions of a bivalent glycoconjugate. This

• regulation of the ligand-receptor interaction. Experimental Docking studies Computer-aided modeling to estimate the spacer lengths of a bivalent glycopeptide ligand to allow bridging of two putative binding sites on FimH was carried out using FlexX flexible docking and consensus scoring, implemented in Sybyl

Dipyridodiazepinone derivatives; synthesis and anti HIV-1 activity

• Nisachon Khunnawutmanotham,
• Nitirat Chimnoi,
• Arunee Thitithanyanont,
• Patchreenart Saparpakorn,
• Kiattawee Choowongkomon,
• Pornpan Pungpo,
• Supa Hannongbua and
• Supanna Techasakul

Beilstein J. Org. Chem. 2009, 5, No. 36, doi:10.3762/bjoc.5.36

• groups in 7 and 8 led to diminished activity relative to that of 5 and 6. 10 and 11, 8-amino analogues of nevirapine, were found to be ineffective inhibitors. Molecular docking To understand the binding mode of the new potent derivatives 5, 6 and 9 were docked into the HIV-1 RT binding site by using the

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole- based inhibitors of neuronal nitric oxide synthase

• Graham R. Lawton,
• Haitao Ji,
• Pavel Martásek,
• Linda J. Roman and
• Richard B. Silverman

Beilstein J. Org. Chem. 2009, 5, No. 28, doi:10.3762/bjoc.5.28

• -groups at the 5-position of 4 should allow us to probe the hydrophobic binding pocket defined by P565, A566, V567, and F584 in the substrate binding site and optimize this interaction. Figure 2 shows the docking mode for 3 and 4a in rat nNOS. Initially, attempts were made to construct 3 and 4 using

• -aminothiazole analogs 3 and 4a-c. A: The docking conformation of 3 in the active site of rat nNOS; B: The docking conformation of 4b in the active site of rat nNOS. Cofactors heme and H4B are shown in orange and purple, respectively. Attempts to open epoxide 5 with deprotonated aminothiazoles. i) n-BuLi, 2