NMR approaches in structure-based lead discovery: recent developments and new frontiers for targeting multi-protein complexes

David M. Dias, Alessio Ciulli (Lead / Corresponding author)

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    Abstract

    Nuclear magnetic resonance (NMR) spectroscopy is a pivotal method for structure-based and fragment-based lead discovery because it is one of the most robust techniques to provide information on protein structure, dynamics and interaction at an atomic level in solution. Nowadays, in most ligand screening cascades, NMR-based methods are applied to identify and structurally validate small molecule binding. These can be high-throughput and are often used synergistically with other biophysical assays. Here, we describe current state-of-the-art in the portfolio of available NMR-based experiments that are used to aid early-stage lead discovery. We then focus on multi-protein complexes as targets and how NMR spectroscopy allows studying of interactions within the high molecular weight assemblies that make up a vast fraction of the yet untargeted proteome. Finally, we give our perspective on how currently available methods could build an improved strategy for drug discovery against such challenging targets.
    Original languageEnglish
    Pages (from-to)101-112
    Number of pages12
    JournalProgress in Biophysics and Molecular Biology
    Volume116
    Issue number2-3
    DOIs
    Publication statusPublished - Nov 2014

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    Protein Transport
    Magnetic Resonance Spectroscopy
    Drug Discovery
    Proteome
    Proteins
    Molecular Weight
    Ligands
    Lead

    Cite this

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    abstract = "Nuclear magnetic resonance (NMR) spectroscopy is a pivotal method for structure-based and fragment-based lead discovery because it is one of the most robust techniques to provide information on protein structure, dynamics and interaction at an atomic level in solution. Nowadays, in most ligand screening cascades, NMR-based methods are applied to identify and structurally validate small molecule binding. These can be high-throughput and are often used synergistically with other biophysical assays. Here, we describe current state-of-the-art in the portfolio of available NMR-based experiments that are used to aid early-stage lead discovery. We then focus on multi-protein complexes as targets and how NMR spectroscopy allows studying of interactions within the high molecular weight assemblies that make up a vast fraction of the yet untargeted proteome. Finally, we give our perspective on how currently available methods could build an improved strategy for drug discovery against such challenging targets.",
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    AU - Ciulli, Alessio

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