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Carsten Schmuck

Publications and source records attributed to Carsten Schmuck.

At least 19 recordsLinked to original sources
PubMed2006

Sequence-dependent binding of dipeptides by an artificial receptor in water.

An artificial dipeptide receptor (1) was designed and observed to bind the deprotonated dipeptide Ac-D-Ala-D-Ala-OH in buffered water with K = 33,100 M(-1), whereas other dipeptides such as Ac-Gly-Gly-OH or Ac-D-Val-D-Val-OH were bound less efficiently, by factors of more than 10 (K < 3000 M(-1)). The efficient binding and the pronounced sequence selectivity are the result of a combination of strong electrostatic contacts and size-discriminating hydrophobic interactions. To provide such a combination, a guanidiniocarbonylpyrrole cation was attached to a novel cyclotribenzylene-substituted alanine derivative 5, to provide a hydrophobic bowl-shaped cavity just large enough to bind a methyl group but not any larger alkyl chains, thus causing the receptor to prefer alanine to valine. We describe the synthesis of 1 and the evaluation of its complexation properties in UV and fluorescence titration studies.

Binding Sites↗
PubMed2006

Ion pair driven self-assembly of a flexible bis-zwitterion in polar solution: formation of discrete nanometer-sized cyclic dimers.

The self-complementary flexible bis-zwitterion 1 forms discrete nanometer-sized cyclic dimers via ion pair driven self-assembly even in polar solvents. The existence of such dimers was confirmed by DOSY NMR, FAB-MS, and scattering experiments (DLS, SANS) which all indicate the concentration-dependent formation of cyclic dimers with a hydrodynamic radius of rH approximately 2.5 nm in solution.

Journal Article↗
PubMed2006

One-armed artificial receptors for the binding of polar tetrapeptides in water: probing the substrate selectivity of a combinatorial receptor library.

We have recently developed a new class of one-armed artificial receptors 1 for the binding of the polar tetrapeptide N-Ac-D-Glu-L-Lys-D-Ala-D-Ala-OH (EKAA) 2 in water using a combined combinatorial and statistical approach. We have now further probed the substrate selectivity of this receptor library 1 by screening a second tetrapeptide substrate (3) with the inverse sequence N-Ac-D-Ala-D-Ala-L-Lys-D-Glu-OH (AAKE). This "inverse" substrate is also efficiently bound by our receptors, with K(ass) approximately 6000 M(-1) for the best receptors, as determined both by a quantitative on-bead binding assay and by UV and fluorescence titration studies in free solution. Hence, the inverse tetrapeptide 3 is in general bound two to three times less efficiently than the "normal" peptide 2 (K(ass) approximately 17,000 M(-1)), even though the complexation mainly involves long-range electrostatic interactions and both the receptor and substrate are rather flexible. Molecular modeling and ab initio calculations have been used to rationalize the observed substrate selectivity and to analyze the various binding interactions within the complex.

Combinatorial Chemistry Techniques↗
PubMed2005

A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods.

The coronavirus main protease, M(pro), is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M(pro) inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M(pro) inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K(i) value of 35.3 muM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.

Amides↗
PubMed2005

"Knock-out" analogues as a tool to quantify supramolecular processes: a theoretical study of molecular interactions in guanidiniocarbonyl pyrrole carboxylate dimers.

It was recently shown experimentally that 5-(guanidiniocarbonyl)-1H-pyrrole-2-carboxylate 1, a self-complementary zwitterion, dimerizes even in water with an unprecedented high association constant of K = 170 M(-1) (J. Am. Chem. Soc. 2003, 125, 452-459). To get an insight into the importance of the various noncovalent binding interactions and of their interplay (electrostatic interactions, hydrogen binding, cooperative effects), we employ density functional theory to study the stability of several "knock-out" analogues in which single hydrogen bonds within these multiple point binding motif are switched off by replacing N-H hydrogen-donor groups with either methylene groups or an oxygen ether bridge. The influence of a highly polar solvent on the dimer stabilities is also examined. These calculations reproduce the experimental data for zwitterion 1. A comparison of 1 with the arginine dimer shows that the energy contents of the monomers also significantly influence the dimer stabilities. The analysis of the various "knock-out" analogues reveals as a main conclusion that simple models either based just on hydrogen-bond counting or on the assumption that the charge interaction by itself is the main and dominant factor fail to explain the stability of such self-assembled dimers. Our computations show that the hydrogen-bond network, the electrostatic attraction, and also their mutual interactions are responsible for the high stability of zwitterion 1.

Journal Article↗
PubMed2005

Recognition of anionic carbohydrates by an artificial receptor in water.

A tris-cationic artificial receptor 1 efficiently binds anionic carbohydrates even in aqueous solution as shown by NMR and UV titration experiments. Complex formation involves both ion pair formation and H-bonds to the sugar, explaining the preference for saccharides compared to simple anions and the observed selectivities among different sugars. [structure: see text]

Carbohydrate Conformation↗
PubMed2005

Efficient complexation of N-acetyl amino acid carboxylates in water by an artificial receptor: unexpected cooperativity in the binding of glutamate but not aspartate.

A new tris-cation 1 binds N-acetyl amino acid carboxylates in water even at millimolar salt concentrations with Kass approximately 103 M-1 due to a clustering of electrostatic interactions. Binding is efficient enough to allow a naked-eyed detection using an indicator displacement assay. Furthermore, receptor 1 shows an unexpected 2:1 complex formation with strong positive cooperativity with glutamate but not aspartate.

Aspartic Acid↗
PubMed2005

A molecular flytrap for the selective binding of citrate and other tricarboxylates in water.

The synthesis and binding properties of a new tricationic guanidiniocarbonyl pyrrole receptor 7 are described. Receptor 7 binds citrate 9 and other tricarboxylates such as trimesic acid tricarboxylate 8 with unprecedented high association constants of K(assoc) > 10(5) M(-1) in water as determined by UV and fluorescence tritration studies. According to NOESY experiments and molecular modeling calculations, the tricarboxylates are bound within the inner cavity of receptor 7 by ion pairing between the carboxylate groups and the guanidiniocarbonyl pyrrole moieties, favored by the nonpolar microenvironment of the cavity. Hence, receptor 7 can be regarded as a molecular flytrap. In the case of the aromatic tricarboxylate 8, additional aromatic interactions further strengthen the complex. The complexes with the tricarboxylates are so strong that even the presence of a large excess of competing anions or buffer salts does not significantly affect the association constant. For example, the association constant for citrate changes only from K(assoc) = 1.6 x 10(5) M(-1) in pure water to K(assoc) = 8.6 x 10(4) M(-1) in the presence of a 170-fold excess of bis-tris buffer and a 1000-fold excess of chloride. This makes 7 one of the most efficient receptors for the binding of citrate in aqueous solvents reported thus far.

Journal Article↗
PubMed2005

Amino acid binding by 2-(guanidiniocarbonyl)pyridines in aqueous solvents: a comparative binding study correlating complex stability with stereoelectronic factors.

A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M(-1) as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2 b and the bound substrate also disfavor complexation.

Amino Acids↗
PubMed2003

N'-alkylated guanidiniocarbonyl pyrroles: new receptors for amino acid recognition in water.

[reaction: see text] N'-Substituted guanidiniocarbonyl pyrroles 7 were synthesized for the first time by activation of a Boc-protected guanidiniocarbonyl pyrrole 3 with triflic anhydride and subsequent reaction with a primary amine. These guanidinium cations are efficient receptors for the complexation of amino acid carboxylates even in water (K(assoc) > 10(3) M(-1)) as could be shown by UV titration studies.

Alkylation↗