Authors: Softley CA, Bostock MJ, Popowicz GM, Sattler M
Abstract
The presence of an unpaired electron in paramagnetic molecules generates significant effects in NMR spectra, which can be exploited to provide restraints complementary to those used in standard structure-calculation protocols. NMR already occupies a central position in drug discovery for its use in fragment screening, structural biology and validation of ligand-target interactions. Paramagnetic restraints provide unique opportunities, for example, for more sensitive screening to identify weaker-binding fragments. A key application of paramagnetic NMR in drug discovery, however, is to provide new structural restraints in cases where crystallography proves intractable. This is particularly important at early stages in drug-discovery programs where crystal structures of weakly-binding fragments are difficult to obtain and crystallization artefacts are probable, but structural information about ligand poses is crucial to guide medicinal chemistry. Numerous applications show the value of paramagnetic restraints to filter computational docking poses and to generate interaction models. Paramagnetic relaxation enhancements (PREs) generate a distance-dependent effect, while pseudo-contact shift (PCS) restraints provide both distance and angular information. Here, we review strategies for introducing paramagnetic centers and discuss examples that illustrate the utility of paramagnetic restraints in drug discovery. Combined with standard approaches, such as chemical shift perturbation and NOE-derived distance information, paramagnetic NMR promises a valuable source of information for many challenging drug-discovery programs.
PMID: 32524233 [PubMed - as supplied by publisher]
Paramagnetic NMR in drug discovery
Paramagnetic NMR in drug discovery
Abstract
The presence of an unpaired electron in paramagnetic molecules generates significant effects in NMR spectra, which can be exploited to provide restraints complementary to those used in standard structure-calculation protocols. NMR already occupies a central position in drug discovery for its use in fragment screening, structural biology and validation of ligandâ??target interactions. Paramagnetic restraints provide unique opportunities, for example, for more sensitive screening to identify weaker-binding...
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06-11-2020 06:01 PM
New Structure of Key Protein Holds Clues for Better Drug Design - Drug Discovery & Development
New Structure of Key Protein Holds Clues for Better Drug Design - Drug Discovery & Development
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Drug Discovery & Development
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New Structure of Key Protein Holds Clues for Better Drug Design
Drug Discovery & Development
To solve this problem, the researchers used a technique called nuclear magnetic resonance (NMR) spectroscopy, which creates strong magnetic fields to locate the positions of probes in a sample. Wüthrich is a...
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01-29-2018 01:57 PM
New Protein Evolution Insight Could Improve Drug Design - Drug Discovery & Development
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New Protein Evolution Insight Could Improve Drug Design
Drug Discovery & Development
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New Protein Evolution Insight Could Improve Drug Design - Drug Discovery & Development
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10-01-2013 09:43 AM
Researchers Look at Averting Drug Resistance - Drug Discovery & Development
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Researchers Look at Averting Drug Resistance
Drug Discovery & Development
Kern and her team studied the protein using nuclear magnetic resonance spectroscopy, adding a drug mimetic in order to learn how the structure EmrE was designed and how it functioned as it was transportingâ??moving the drug from the inside of the cell ...
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02-02-2012 09:43 PM
[NMR paper] NMR in the acceleration of drug discovery.
NMR in the acceleration of drug discovery.
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Curr Opin Drug Discov Devel. 2001 Jul;4(4):479-92
Authors: Sem DS, Pellecchia M
The field of NMR spectroscopy has grown beyond expectations from the first historic observation of nuclear magnetic resonance in 1946 by Bloch and Purcell, to the first generation of protein structures 20 years ago, to the present where NMR structures now represent 15 to 20% of those submitted to the Protein Data Bank (PDB). However, the applications of NMR go far...
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11-19-2010 08:44 PM
[NMR paper] Applications of NMR in drug discovery.
Applications of NMR in drug discovery.
Related Articles Applications of NMR in drug discovery.
Drug Discov Today. 2000 Jun;5(6):230-240
Authors: Roberts GC
In the half-century since its discovery, nuclear magnetic resonance (NMR) has become the single most powerful form of spectroscopy in both chemistry and structural biology. The dramatic technical advances over the past 10-15 years, which continue apace, have markedly increased the range of applications for NMR in the study of protein-ligand interactions. These form the basis for its most...
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11-18-2010 09:15 PM
[NMR paper] Flow NMR spectroscopy in drug discovery.
Flow NMR spectroscopy in drug discovery.
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Curr Opin Drug Discov Devel. 2000 May;3(3):269-74
Authors: Stockman BJ
Flow NMR spectroscopy techniques are becoming increasingly utilized in drug discovery and development. LC-NMR has become a routine method to resolve and identify mixture components. It has broad applications in natural products biochemistry, and drug metabolism and toxicology studies. The rapid throughput of direct-injection NMR of biofluids, combinatorial chemistry samples...
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[NMR paper] NMR screening in drug discovery.
NMR screening in drug discovery.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif Related Articles NMR screening in drug discovery.
Curr Opin Biotechnol. 1999 Feb;10(1):54-8
Authors: Moore JM
NMR methods in drug discovery have traditionally been used to obtain structural information for drug targets or target-ligand complexes. Recently, it has been shown that NMR may be used as an alternative approach for identification of ligands that bind to protein drug targets, shifting the emphasis...
Paramagnetic NMR in drug discovery.
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