Molecular modeling and design of regioselectively addressable functionalized templates with rigidified three-dimensional structures

Nikiforovich, Gregory V.; Mutter, Manfred; Lehmann, Christian W.

doi:10.1002/(sici)1097-0282(19991005)50:4<361::aid-bip2>3.0.co;2-3

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…In contrast, for the AspProGlyAsp (DPGD) motif, characteristic elements of a type II and a type I β‐turn structure are simultaneously observed: ROE cross‐peaks are detected between Gly10 NH and Pro9 Hα (2.1 Å), as well as between Gly10 NH and Pro9 Hδ (2.9 Å), and Gly10 NH and Pro9 Hγ2 (3.1 Å). These data can be explained by a conformational equilibrium between these two limiting forms of β‐turns, as proposed by Mutter and co‐workers who performed simulations on similar molecules 30…”

Section: Resultssupporting

confidence: 56%

Mechanistic Investigation of the 2,5‐Diphenylpyrrolidine‐Catalyzed Enantioselective α‐Chlorination of Aldehydes

Halland

Lie

Kjærsgaard

et al. 2005

Chemistry A European J

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The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly. Furthermore, the rate-determining step in the overall reaction was determined and the presence of nonlinear effects was probed.

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Section: Resultssupporting

confidence: 56%

Mechanistic Investigation of the 2,5‐Diphenylpyrrolidine‐Catalyzed Enantioselective α‐Chlorination of Aldehydes

Halland

Lie

Kjærsgaard

et al. 2005

Chemistry A European J

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“…These data can be explained by a conformational equilibrium between these two limiting forms of b-turns, as proposed by Mutter and co-workers who performed simulations on similar molecules. [30] To check that the four carboxyl functions of the side chains of the glutamic (Glu3 and Glu6) and aspartic acids (Asp1 and Asp8) are well-positioned to complex Ln 3 + , 100 structures were calculated by using X-PLOR. [31] A superimposition of the 10 lowest-energy structures is shown [32] in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

A Gadolinium‐Binding Cyclodecapeptide with a Large High‐Field Relaxivity Involving Second‐Sphere Water

Bonnet

Fries

Crouzy³

et al. 2009

Chemistry A European J

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A new cyclodecapeptide incorporating two prolylglycine sequences as beta-turn inducers and bearing four side chains with acidic carboxyl groups for cation complexation has been prepared. Structural analysis in water by (1)H NMR spectroscopy and CD shows that this template adopts a conformation suitable for the complexation of lanthanide ions Ln(3+), with its carboxyl groups oriented on the same face of the peptide scaffold. Luminescence titrations show that mononuclear Ln-PA complexes are formed with apparent stability constants of log beta(110) approximately 6.5 (pH 7). The high-field water relaxivity values arising from the Gd-PA complex at 200-500 MHz have been interpreted with molecular parameters determined independently. The experimentally determined water relaxivities are undoubtedly 30% higher than the expected values for this complex with two inner-sphere (IS) water molecules and a medium-range rotational correlation time (tau(R) = 386 ps (+/-10%)). This led us to propose the existence of a large second-sphere (2S) contribution to the relaxivity caused by the interaction of water molecules with the hydrophilic peptide ligand by hydrogen-bonding.

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The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an ω-conotoxin mimic

Pallaghy¹,

Norton²

2000

Biopolymers

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Contryphan‐R, from venom of the cone‐shell Conus radiatus, represents a novel cyclic peptide scaffold onto which residues may be grafted to mimic unrelated protein surfaces. Three substitutions were made at the x and X positions of the disulfide‐bridged motif CPxXPXC, where X and x represent any L‐ and D‐handed residues, respectively, P represents proline or hydroxyproline, and C a half‐cystine. These substitutions were designed to mimic part of the pharmacophore of the unrelated globular polypeptide ω‐conotoxin GVIA, which blocks N‐type calcium channels. The structure of this engineered contryphan, YNK‐contryphan‐R ([D‐Tyr4, Asn5, Lys7]contryphan‐R), is shown to be similar to that of native contryphan‐R (Pallaghy et al., Biochemistry, 1999, Vol. 38, pp. 13553–13559), confirming that the scaffold is robust with respect to the multiple substitutions. In particular, the α–β bond vectors characterising the orientation of the side chains relative to the backbone are similar in contryphan‐R, YNK‐contryphan‐R, and ω‐conotoxin GVIA, which is the required result for a scaffold‐based approach to molecular design. The solution structure of YNK‐contryphan‐R has an N‐terminal, nonhydrogen‐bonded, chain reversal centered on Hyp3–D‐Trp4, and a C‐terminal type I β‐turn. A minor form due to cis–trans isomerism of the Hyp2–Cys3 peptide bond is present in YNK‐contryphan‐R in a larger proportion than in contryphan‐R. It is evident, particularly from the 3JHαHN coupling constants, that YNK‐contryphan‐R is more flexible than contryphan‐R, probably due to the absence in YNK‐contryphan‐R of the Pro–Trp packing present in the native molecule. Nevertheless, the structure confirms that cyclic peptide molecular designs can achieve the intended conformations. © 2000 John Wiley & Sons, Inc. Biopoly 54: 173–179, 2000

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Molecular modeling and design of regioselectively addressable functionalized templates with rigidified three-dimensional structures

Cited by 7 publications

References 38 publications

Mechanistic Investigation of the 2,5‐Diphenylpyrrolidine‐Catalyzed Enantioselective α‐Chlorination of Aldehydes

Mechanistic Investigation of the 2,5‐Diphenylpyrrolidine‐Catalyzed Enantioselective α‐Chlorination of Aldehydes

A Gadolinium‐Binding Cyclodecapeptide with a Large High‐Field Relaxivity Involving Second‐Sphere Water

The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an ω-conotoxin mimic

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