G-Protein coupled receptors: answers from simulations

• Timothy Clark

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

• variations of metadynamics allow very effective use of massively parallel supercomputers in order to investigate ligand binding and unbinding and transitions between active and inactive receptor conformations. Indeed, the power of modern simulations is such that we must revisit the relationship between

• receptors in 2011 [31]. Notably, these simulations were performed on Anton, a specially constructed computer for MD simulations [32], and were unconstrained, so that they simulated the ligand-binding process without enhanced sampling on a time scale of several μs. Later simulations of the same type revealed

• functional bias and activate one or other of the two alternative paths. Metadynamics simulations have proven to be able to determine the bias, or lack of it, by considering the change in ligand-binding free energy between the binary ligand–receptor complex and the alternative ternary complexes with either

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• comparison to other glycoclusters, i.e., glycolipid micelles and glycoproteins, which allows an ordered, controlled and stable tridimensional presentation of the ligands, providing higher ligand binding capacity [6][96]. For this reason, they represent an ideal scaffold to study the activation of the immune

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

• 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

• empirical scoring functions, namely Bohm’s scoring function [127], SCORE and ChemScore. Another example of consensus scoring is MultiScore [128]. This score function is a combination of eight different scoring functions and have shown improved protein–ligand binding affinities. Protein–ligand docking

• of drug molecules. These changes may involve overall backbone structure rearrangements or they can be subtle where only the side chains near the ligand binding site change to accommodate the bound ligand. However, this dynamic nature of targets is frequently ignored and protein flexibility is

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

• levels, suggesting that pieC is not essential for biosynthesis [164]. PieC belongs to the SRPBCC superfamily, which has previously been shown to be involved in the controlled cyclisation events catalysed by type II PKS [167][168]. These enzymes have a deep hydrophobic ligand-binding pocket, which

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

• order to further explore the possibility that compound 4 may act as a LasR antagonist, it was subjected to molecular docking studies against the P. aeruginosa LasR ligand–binding domain (LBD) [31]. Specifically, both OdDHL and 4 were docked into the OdDHL binding pocket of two LasR LBD structures, one

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

• squaric ester monoester 4 6900 times higher [15], and the indolinylphenyl mannoside 5 arrives at an IC50 of 2.4 nM [8]. Cartoon illustrating ligand binding by the bacterial lectin FimH. Complexation of D-manno-configured C-glycosyl-type glycoconjugates inside the carbohydrate recognition domain (CRD) of

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

• matched in order to balance enthalpic gain with entropic loss of the system. In such a setting, a rigid multivalent ligand binding to a flexible receptor can be expected to reduce the entropy of the system upon binding, and thus will result in a partial or complete loss of the multivalent affinity

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

• inclusion complex. The ligand binding mode and water accessibility, host–guest interaction, and binding free energy of the inclusion complex were analyzed. The MM-PBSA/GBSA and M06-2X/6-31G(d,p)//MM-PBSA/GBSA approaches were used to predict the binding affinity of fisetin/β-CD complexes. The M06-2X/6-31G(d

Microsolvation and sp²-stereoinversion of monomeric α-(2,6-di-tert-butylphenyl)vinyllithium as measured by NMR

• Rudolf Knorr,
• Monika Knittl and
• Eva C. Rossmann

Beilstein J. Org. Chem. 2014, 10, 2521–2530, doi:10.3762/bjoc.10.263

• molar equivalent of TMEDA. Although the severely broadened NCH2 and NCH3 signals did not enable us to differentiate between a symmetric (chelating) and an unsymmetrical (nonchelating) ligand binding of TMEDA at lithium, we are sure to have met the chelating mode which must be favored over the

Photoswitchable precision glycooligomers and their lectin binding

• Daniela Ponader,
• Sinaida Igde,
• Marko Wehle,
• Katharina Märker,
• Mark Santer,
• David Bléger and
• Laura Hartmann

Beilstein J. Org. Chem. 2014, 10, 1603–1612, doi:10.3762/bjoc.10.166

• modelling for ligand binding. Ongoing studies further investigate ligand binding by additional techniques such as isothermal titration calorimetry and fluorescence spectroscopy. Overall, we have successfully developed photoswitchable glycomimetics that allow for a stimulus-induced change in binding affinity

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

• , Figure 3) [3][36]. These photoaffinity ligands were found to retain the ability to modulate dopamine receptors to varying degrees, thus indicating that the incorporation of the photoreactive moieties did not have a significantly adverse effect on ligand binding to the modulatory site. Cross-linking of

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

• relaxation properties of a small-molecular-weight reporter ligand that reversibly binds to a ligand binding domain, which in turn is fused to the interacting protein of interest. Subsequent protein–protein interaction leads to an additional increase of the molecular weight of the complex and can efficiently

• compound lacking the affinity to the ligand binding domain. Here we describe the possibility of monitoring protein interactions by 19F NMR, known as fluorine chemical-shift anisotropy and exchange for screening (FAXS) [5][6][7], with internal control by using 2-F labeled maltose as a reporter system. The

• 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

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

• shown both by MS/MS studies and by affino dot–blot analysis. Keywords: diazirines; FimH; lectins; MS/MS analysis; photoactive mannoside ligands; photoaffinity labeling; Introduction Photoaffinity labeling is a technique by which ligand binding sites of a receptor protein can be identified in solution

• ) ppm. MALDI-TOF-MS: m/z = 855.3 [M + Na]+; ESI-MS: m/z = 827.31 [M – N2 + Na]+; 855.31 [M + Na]+ (832.85 calcd. for C34H47F3N8O11S). The photoaffinity technique allows the identification of ligand binding sites of a receptor protein after photo-crosslinking, proteolysis and affinity chromatography. a

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

• 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

Flexible synthesis of poison- frog alkaloids of the 5,8-disubstituted indolizidine- class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

• Soushi Kobayashi,
• Naoki Toyooka,
• Dejun Zhou,
• Hiroshi Tsuneki,
• Tsutomu Wada,
• Toshiyasu Sasaoka,
• Hideki Sakai,
• Hideo Nemoto,
• H. Martin Garraffo,
• Thomas F. Spande and
• John W. Daly

Beilstein J. Org. Chem. 2007, 3, No. 30, doi:10.1186/1860-5397-3-30

• , learning and memory. [5][6] Some ligand-binding and autoradiography studies with postmortem human brain suggest that loss of neuronal nicotinic receptors is related to central cholinergic disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia. [4][6] For instance, in schizophrenic

• patients, decrease in binding of α-bungarotoxin (α-Bgt), a major specific ligand for α7 nicotinic receptors, has been detected in hippocampus, thalamus and frontal cortex [16][17]. Therefore, loss of α7 nicotinic ligand-binding appears to be an early presymptomatic diagnostic marker for schizophrenia. For