Authors: Jahnke W, Flörsheimer A, Blommers MJ, Paris CG, Heim J, Nalin CM, Perez LB
One of the prime merits of NMR as a tool for lead finding in drug discovery research is its sensitivity and robustness to detect weak protein-ligand interactions. This sensitivity allows to build up ligands for a given target in a modular way, by a fragment-based approach. In this approach, two ligands are seperately identified which bind to the target protein generally weakly, but at adjacent binding sites. In a next step, they are chemically linked to produce a high-affinity ligand. This review discusses methods to detect "second-site" ligands that bind to a protein in the presence of a "first-site" ligand, and methods to elucidate structural details on the spatial orientation of both ligands, so that chemical linkage is based on a large piece of experimental information. Published examples from second-site screening and linker design are summarized, and are complemented by previously unpublished in-house examples.
[NMR paper] The application of x-ray, NMR, and molecular modeling in the design of MMP inhibitors
The application of x-ray, NMR, and molecular modeling in the design of MMP inhibitors.
Related Articles The application of x-ray, NMR, and molecular modeling in the design of MMP inhibitors.
Curr Top Med Chem. 2004;4(12):1311-27
Authors: Rush TS, Powers R
The following review discusses the successful application of X-ray, NMR, and molecular modeling in the design of potent and selective inhibitors of matrix metalloproteinases (MMPs) and TNFalpha-converting enzyme (TACE) from Wyeth. The importance of protein and ligand mobility as it impacts...
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11-24-2010 09:25 PM
[NMR paper] Exploring the active site of human factor Xa protein by NMR screening of small molecu
Exploring the active site of human factor Xa protein by NMR screening of small molecule probes.
Related Articles Exploring the active site of human factor Xa protein by NMR screening of small molecule probes.
Org Biomol Chem. 2003 Dec 7;1(23):4235-41
Authors: Fielding L, Fletcher D, Rutherford S, Kaur J, Mestres J
A collection of small molecules (MW < 350 Da) was screened for binding to human factor Xa using saturation transfer difference NMR spectroscopy to detect binding. The NMR screening experiments identified four hits. Binding isotherms...
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11-24-2010 09:16 PM
[NMR paper] The linker histone homolog Hho1p from Saccharomyces cerevisiae represents a winged he
The linker histone homolog Hho1p from Saccharomyces cerevisiae represents a winged helix-turn-helix fold as determined by NMR spectroscopy.
Related Articles The linker histone homolog Hho1p from Saccharomyces cerevisiae represents a winged helix-turn-helix fold as determined by NMR spectroscopy.
Nucleic Acids Res. 2003 Dec 15;31(24):7199-207
Authors: Ono K, Kusano O, Shimotakahara S, Shimizu M, Yamazaki T, Shindo H
Hho1p is assumed to serve as a linker histone in Saccharomyces cerevisiae and, notably, it possesses two putative globular...
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11-24-2010 09:16 PM
[NMR paper] Site-selective labeling strategies for screening by NMR.
Site-selective labeling strategies for screening by NMR.
Related Articles Site-selective labeling strategies for screening by NMR.
Comb Chem High Throughput Screen. 2002 Dec;5(8):623-30
Authors: Weigelt J, Wikström M, Schultz J, van Dongen MJ
NMR based screening has become an important tool in the pharmaceutical industry. Methods that provide information on the location of small molecule binding sites on the surface of a drug target (e. g. SAR-by-NMR and related techniques) are of particular interest. In order to extend the applicability of...
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11-24-2010 08:58 PM
[NMR paper] Site-selective screening by NMR spectroscopy with labeled amino acid pairs.
Site-selective screening by NMR spectroscopy with labeled amino acid pairs.
Related Articles Site-selective screening by NMR spectroscopy with labeled amino acid pairs.
J Am Chem Soc. 2002 Mar 20;124(11):2446-7
Authors: Weigelt J, van Dongen M, Uppenberg J, Schultz J, Wikström M
A new method for site-selective screening by NMR is presented. The core of the new method is the dual amino acid sequence specific labeling technique. Amino acid X is labeled with (13)C and amino acid Y is labeled with (15)N. Provided only one XY pair occurs in the...
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11-24-2010 08:49 PM
Oligo design tools for gene synthesis
Oligo design tools for gene synthesis
1 DNAWorks: http://helixweb.nih.gov/dnaworks/
2 TmPrime: http://prime.ibn.a-star.edu.sg/
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Proteins
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08-25-2010 04:37 AM
[NMR paper] Import, processing, and two-dimensional NMR structure of a linker-deleted signal pept
Import, processing, and two-dimensional NMR structure of a linker-deleted signal peptide of rat liver mitochondrial aldehyde dehydrogenase.
Related Articles Import, processing, and two-dimensional NMR structure of a linker-deleted signal peptide of rat liver mitochondrial aldehyde dehydrogenase.
J Biol Chem. 1993 Sep 15;268(26):19906-14
Authors: Thornton K, Wang Y, Weiner H, Gorenstein DG
Previous NMR studies (Karslake, C., Piotto, M. E., Pak, Y. M., Weiner, H., and Gorenstein, D. G. (1990) Biochemistry 29, 9872-9878) had shown that a 22-amino...
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08-22-2010 03:01 AM
[NMR paper] NMR spectroscopy in structure-based drug design.
NMR spectroscopy in structure-based drug design.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif Related Articles NMR spectroscopy in structure-based drug design.
Curr Opin Biotechnol. 1999 Feb;10(1):42-7
Authors: Roberts GC
NMR methods for the study of motion in proteins continue to improve, and a number of studies of protein-ligand complexes relevant to drug design have been reported over the past year, for example, studies of fatty-acid-binding protein and SH2 and SH3 domains. These...
Second-site NMR screening and linker design.
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