Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• modulatory binding site in a different manner than 2 and its analogues [33]. Possible support for such a hypothesis can be seen in the different activity profiles of α,α-disubstituted glycine analogues of PLG and the corresponding α,α-disubstituted derivatives of lactam PLG peptidomimetic 2 [35]. In addition

• changes when these ligands bound to the allosteric binding site. This in turn produced different conformational effects at the orthosteric site where the dopamine receptor agonists bind. To test this hypothesis, the syntheses of β-dimethyl derivatives of 29a, 29b, 49a, and 49b, i.e., spiro-bicyclic

• analogues of 2 in which lipophilic moieties were incorporated into the structure to mimic the isobutyl side chain of the leucyl residue of PLG yielded analogues 10–12 (Figure 2) with increased activity, suggesting that the lipophilic side chain was enhancing the binding of the compounds to the PLG binding

Influence of cyclodextrin on the solubility and the polymerization of (meth)acrylated Triton^® X-100

• Melanie Kemnitz and
• Helmut Ritter

Beilstein J. Org. Chem. 2012, 8, 2176–2183, doi:10.3762/bjoc.8.245

• Triton® X-100 are reported in literature. In our previous paper, the coexistence of a 1:1 and 2:1 complex with an extraordinary high (K1 = 1.71 × 105 M−1) and a lower equilibrium constant (K2 = 260 M−1) was described [12]. Due to the fact that the tert-octyl group represents the preferred binding site of

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• the side chains in the small heterodet peptide ring are known to be involved in actin binding they were not used for derivatization. In the larger peptide ring, on the other hand, the dihydroxylated leucine moiety is juxtaposed to the actin binding site and thus appeared as most promising for

Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

• Julia Meier,
• Kristin Kassler,
• Heinrich Sticht and
• Jutta Eichler

Beilstein J. Org. Chem. 2012, 8, 1858–1866, doi:10.3762/bjoc.8.214

• Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability

• -amino acids. Keywords: biomimetic synthesis; CD4; HIV entry; peptide; protein binding site; Introduction Synthetic molecules that have the ability to mimic binding and/or functional sites of proteins are useful tools for exploring and modulating protein function, as they interfere with binding events

• protein binding site mimics. We have previously developed strategies for the design and generation of scaffolded and assembled peptides to generate protein binding site mimics [1]. The interaction of the HIV-1 envelope glycoprotein gp120 with its cellular receptor CD4 is the first step in the process of

Mannose-decorated cyclodextrin vesicles: The interplay of multivalency and surface density in lectin–carbohydrate recognition

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2012, 8, 1543–1551, doi:10.3762/bjoc.8.175

• observed around a mannose surface density of 50%: if the mannose density is reduced even further, the average distance of the mannose units on the vesicle surface is larger than the binding site separation of ConA, and hence multivalent interaction is no longer observed. The average distance between two

• cyclodextrins at the vesicle surface is approximately 2.2 nm [30]. The distance between two mannose molecules is expected to be the same when using a maximum surface coverage of the cyclodextrin host surface with guest 1. The binding site separation for ConA is 3.6 to 4.9 nm [21][22], which roughly corresponds

• surface (dCH) exceeds the binding-site separation of ConA (dBS) [21]. However, the surface density of mannose also decreases if the guest molecule occupies two or even three cyclodextrin cavities but yet carries only one mannose unit (Figure 7). In the case of divalent guest 2 (with two adamantane units

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• the first strategy, because in structures such as (R)-9 the stereogenic center was rather close to the thiourea hydrogen bridge binding site. Scheme 3 summarizes our intended preparative approach towards (R)-9 via N-methyl-α-aminosulfoximine (R)-8, which unfortunately, remained unsuccessful. Heating

• likely serves as binding site for the substrate. Nevertheless, a remarkable enantiomeric ratio of 78:22 has already been achieved in the Biginelli reaction, which is known to be difficult to control. Thus, bringing the sulfonimidoyl group into closer proximity to the thiourea core might be beneficial for

• on the stereochemistry-determining path despite the fact that they were relatively close to the thiourea substrate binding site. Thus, reducing molecular flexibility by incorporation of plain arenes as linkers appears to be more important than conformational fixation through additional stereogenic

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• to β-tubulin monomers at a site overlapping the vinca alkaloid binding site [9]. Recently, we disclosed several mutasynthetic studies aimed at the production of derivatives of ansamitocins 3–5 [10][11][12] as well as of geldanamycin (6), utilizing mutant strains of Actinosynnema pretiosum, the

High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction

• Henning S. G. Beckmann,
• Heiko M. Möller and
• Valentin Wittmann

Beilstein J. Org. Chem. 2012, 8, 819–826, doi:10.3762/bjoc.8.91

• of the triazole moieties as well as the central phenyl ring. This ring strain can be reduced by slightly pulling the GlcNAc residues directly attached to the linker out of the binding site, but at the expense of a less efficient multivalent binding of the two chitobiose entities. The chitobiose

• conformation. Ligand C2, and even more so ligand C3, possess very limited conformational freedom when adopting a chelating binding mode. Conformational changes within the linkers of C2 and C3 lead to forces that pull one or the other GlcNAc/chitobiose out of its binding site. This situation may increase the

• significantly increased conformational freedom. This is expected to facilitate binding in a chelating fashion at relatively low entropic costs. It is important to note that the third chitobiose unit of C6 cannot reach a third carbohydrate binding site of the WGA dimer. The closest distance to another binding

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• on type 1 fimbriae is an attractive target for the inhibition of α-mannose-mediated cell adhesion [127][128][129][130][131]. Previous X-ray studies have proven that the FimH lectin has a monovalent binding site recognizing α-D-mannose [132][133]. In close proximity to the mannose-binding crevice, two

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

• -docking experiments using the cyclic peptide Cilengitide® (cyclo-[RGDfN(Me)V]) [27] as a ligand. The orientation of the pentapeptide Cilengitide and its binding to the binding site formed by the α and β chains of αvβ3 reproduced the published X-ray structure with high accuracy. The method thus validated

• was then used to dock GSF in silico to the same surface area. This resulted in two binding sites. One site was identical to the binding site described for the RGD motif [28] of the cyclic peptide and a second binding site was located inside the β-propeller domain of the αv domain (Figure 4A). This

Synthesis of fluorinated maltose derivatives for monitoring protein interaction by ¹⁹F NMR

• Michaela Braitsch,
• Hanspeter Kählig,
• Georg Kontaxis,
• Michael Fischer,
• Toshinari Kawada,
• Robert Konrat and
• Walther Schmid

Beilstein J. Org. Chem. 2012, 8, 448–455, doi:10.3762/bjoc.8.51

• eight α(1→4)-linked glucose (Glc) units with micromolar affinities [15][16]. X-ray structural data (PDB ID codes 1-DMB and 1ANF) demonstrated that the MBP (370 residues, Mr = 41 kDa) consists of two globular domains joined by a hinge-bending region, in which the ligand binding site is located in a cleft

• between the two domains. MBP exists in two different conformations: The ligand-free “open” form, exposing the binding site, and in the presence of a ligand, the “closed” form, trapping the ligand to provide contacts from both domains [17][18][19]. The number of protein–sugar hydrogen bonds associated with

Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes

• Nora L. Löw,
• Egor V. Dzyuba,
• Boris Brusilowskij,
• Lena Kaufmann,
• Elisa Franzmann,
• Wolfgang Maison,
• Emily Brandt,
• Daniel Aicher,
• Arno Wiehe and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2012, 8, 234–245, doi:10.3762/bjoc.8.24

• amide coupling with 6 yielding binding site 2 in 73% yield. Since an excess of 7 was used and the 2’/6’-positions are sterically hindered, only monoiodination in the 4’-position was observed. This synthetic pathway thus gives reasonable overall yields. It should be mentioned that the diamide moiety

• polar aprotic solvent, such as acetone, acetonitrile, DMF or DMSO, which would solubilize the axles sufficiently well, would interfere strongly with pseudorotaxane formation. The tertiary amides are much more soluble and, therefore, appear to be the more appropriate binding site. However, the better

Fifty years of oxacalix[3]arenes: A review

• Kevin Cottet,
• Paula M. Marcos and
• Peter J. Cragg

Beilstein J. Org. Chem. 2012, 8, 201–226, doi:10.3762/bjoc.8.22

• conformations (cone and partial-cone), and a C3-symmetry [24]. This last feature can provide a suitable binding site for species that require trigonal-planar, tetrahedral or octahedral coordination environments. The flexibility of the macrocycles can allow them to establish ideal bond distances and angles to

• ) methylene groups had a binding affinity for linear primary alkyl ammonium ions from n-BuNH3+ to n-HexNH3+. 3.2 Upper-rim derivatives Although the lower rim has many advantages as a binding site for guests, not least in the relative ease with which substituents can be attached, the upper rim can also

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• artificial system driving endergonic condensations (Figure 1), we draw the conclusion that only one of the binding sites should provide metal coordination to the vanadate (or phosphate) and the other binding site should associate the nucleophilic anion by neutral hydrogen bonds. Similar effects obviously

Impact of the level of complexity in self-sorting: Fabrication of a supramolecular scalene triangle

• Kingsuk Mahata and
• Michael Schmittel

Beilstein J. Org. Chem. 2011, 7, 1555–1561, doi:10.3762/bjoc.7.183

• groups available for coordination in addition to its two bisimine nitrogens. Thus, unit 1 may either act as a strong bidentate, tridentate or tetradentate binding site for zinc(II) ions, and there is no large thermodynamic difference between a [Zn(16)(27)]+-type connection and a [Zn(16)(47)]+-type link

Effects of anion complexation on the photoreactivity of bisureido- and bisthioureido-substituted dibenzobarrelene derivatives

• Heiko Ihmels and
• Jia Luo

Beilstein J. Org. Chem. 2011, 7, 278–289, doi:10.3762/bjoc.7.37

• ], liquid crystals [18], chiral crystals [19][20][21][22][23], or cyclodextrins (CDs) [24][25][26] in such a way that the chiral environment within the binding site has an influence on preferential reaction pathways, thus inducing stereoselective photoreactions. Along these lines, the di-π-methane (DPM

Fluorometric recognition of both dihydrogen phosphate and iodide by a new flexible anthracene linked benzimidazolium-based receptor

• Kumaresh Ghosh and
• Debasis Kar

Beilstein J. Org. Chem. 2011, 7, 254–264, doi:10.3762/bjoc.7.34

• one binding site is present for interaction. Under similar experimental conditions, the emission of 2 was only slightly changed. Figure 8 displays the change in emission of 2 upon addition of 1 equiv of the same anions in CH3CN. In the presence of excess H2PO4− ions, the change in emission of 2 was

• less compared to the case of 1 (see Supporting Information File 1). The quenching of emission of 1 upon complexation is attributed to the activation of a PET process occurring between the binding site and the excited state of anthracene. The Stern–Volmer plot in Figure 9 illustrates the quenching

• ][42][43][44][45]. Iodide binding induced quenching of emission is attributed to the i) complementarity in size of iodide with the pseudocavity formed by the receptor-binding site and ii) heavy atom effect of iodide, which is also true for Br−. But the small quenching of emission in the presence of Br

An easy assembled fluorescent sensor for dicarboxylates and acidic amino acids

• Xiao-bo Zhou,
• Yuk-Wang Yip,
• Wing-Hong Chan and
• Albert W. M. Lee

Beilstein J. Org. Chem. 2011, 7, 75–81, doi:10.3762/bjoc.7.11

• guests, an additional binding site must be introduced. Thus, (S)-phenylalaninol (obtainable from L-phenylalanine) was reacted with isothiocyanate 4 to give sensor 2 in 40% yield. We envisaged that the additional alcohol functionality present in 2 could provide a binding site for the α-amino group of

Anthracene appended pyridinium amide–urea conjugate in selective fluorometric sensing of L-N-acetylvaline salt

• Kumaresh Ghosh,
• Tanmay Sarkar and
• Asoke P. Chattopadhyay

Beilstein J. Org. Chem. 2010, 6, 1211–1218, doi:10.3762/bjoc.6.139

• to the charge–charge interaction and formation of unconventional hydrogen bonds with the anionic guests [27]. In order to explore this binding site for a wide range of substrates, especially for amino acid derivatives, we report here the design and synthesis of a new fluororeceptor 1 where anthracene

• is attached to the binding site through a covalent CH2 spacer to yield a photo induced electron transfer sensory system [28]. The receptor 1 shows effective binding of the tetrabutylammonium salt of L-N-acetylvaline by exhibiting significant change in emission. Complexation induced formation of an

• observation [20]. The different modes of emission (enhancing and quenching) of 1 in the presence of the different guests studied is believed to be due to the structural difference and hydrogen bonding abilities of the guests for which the PET process occurring between the amide-urea binding site and the

Catalysis: transition-state molecular recognition?

• Ian H. Williams

Beilstein J. Org. Chem. 2010, 6, 1026–1034, doi:10.3762/bjoc.6.117

• concept. It is shown that reactant binding is intrinsically inhibitory, and that attempts to design catalysts that focus simply upon attractive interactions in a binding site may fail. Free-energy changes along the reaction coordinate for SN2 methyl transfer catalysed by the enzyme catechol-O-methyl

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

• . It requires a photoactive ligand derivative, which can form a reactive species upon photo-excitation. Thus, incubation of the photoprobe with a protein followed by irradiation can result in a photo-crosslinked product, that provides structural information on the binding site of the protein (Figure 1

• just one monovalent carbohydrate binding site on the FimH protein [9][10][11][12][13]. Thus, we decided to employ photoactive ligands to probe carbohydrate binding to the known CRD in solution and to identify possibly auxiliary, so far unknown, binding sites on bacterial lectin FimH [2]. The known FimH

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

• 1 fimbriae with a monovalent carbohydrate recognition domain (CRD) that is known from X-ray studies. However, binding studies with multivalent ligands have suggested an additional carbohydrate-binding site on this protein. In order to prove this hypothesis, a bivalent glycopeptide ligand with the

• and a pilin domain, which is required for fimbriae assembly [7]. The FimH adhesin domain features a carbohydrate binding site at its tip, called the carbohydrate recognition domain (CRD), which is known from X-ray studies [8][9][10][11]. It is a monovalent binding site, which can accommodate one α-D

• trisaccharide substructures, mainly α-D-Man-(1→3)-[α-D-Man-(1→6)]-D-Man. By employing site directed mutagenesis, it was found that mutations in one of these cavities significantly reduces binding, indicating that this could be a second carbohydrate binding site, relevant for ligand binding [21]. Thus, it was

RAFT polymers for protein recognition

• Alan F. Tominey,
• Julia Liese,
• Sun Wei,
• Klaus Kowski,
• Thomas Schrader and
• Arno Kraft

Beilstein J. Org. Chem. 2010, 6, No. 66, doi:10.3762/bjoc.6.66

• tetramethyl ester was subjected to LiBr-assisted nucleophilic cleavage to furnish the free bisphosphonate dianion binding site. This procedure has two major drawbacks. First, if the functional groups on the polymer backbone become restricted in their accessability, the final deprotection step will suffer from

Anthracene coupled adenine for the selective sensing of copper ions

• Kumaresh Ghosh and
• Tanushree Sen

Beilstein J. Org. Chem. 2010, 6, No. 44, doi:10.3762/bjoc.6.44

• sensor, shown in Figure 1. In both 1 and 2, adenine is defined as the binding site, which is connected to the anthracene probe via –CH2– spacer at the different regions of adenine. In order to find out the possible site for binding of metal ions, we optimized the geometries of both 1 and 2 at AM1 level

• compared to the cases of 1 and 2 with Cu2+. During the interaction process no other changes were observed. This finding thus indicates that the adenine moiety in both 1 and 2 acts as a metal ion binding site for which participation of anthracene in cation-π interaction is facilitated upon binding of metal

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

• stoichiometry between a specific host and guest – or dynamic, where the binding of the first guest to the first binding site of a receptor affects the association constant of a second guest with a second binding site. Either positive allosteric binding – the first guest increases the association constant of the

• “key” in the complementary binding site or an inclusion compound. This host pre-organization leads to a major enhancement of the overall energy of guest complexation. The binding is energetically favored: Both enthalpic – a less solvent accessible area leads to a less strongly solvated guest with fewer

• has been attributed to the tetrahedral binding site geometry that favors complexation of the tetrahedral ammonium ion over that of the spherically symmetrical potassium ion, underlining the particular importance of hydrogen bonding and symmetry considerations in the design of ammonium ion recognition