revisiting biomolecular nmr spectroscopy for promoting small molecule drug discovery

Revisiting biomolecular NMR spectroscopy for promoting small-molecule drug discovery

Affiliations.

• 1 Structure-Based Drug Design Group, Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan. [email protected].
• 2 Structure-Based Drug Design Group, Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan.
• 3 Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.
• PMID: 32306215
• DOI: 10.1007/s10858-020-00314-0

Recently, there has been increasing interest in new modalities such as therapeutic antibodies and gene therapy at a number of pharmaceutical companies. Moreover, in small-molecule drug discovery at such companies, efforts have focused on hard-to-drug targets such as inhibiting protein-protein interactions. Biomolecular NMR spectroscopy has been used in drug discovery in a variety of ways, such as for the reliable detection of binding and providing three-dimensional structural information for structure-based drug design. The advantages of using NMR spectroscopy have been known for decades (Jahnke in J Biomol NMR 39:87-90, (2007); Gossert and Jahnke in Prog Nucl Magn Reson Spectrosc 97:82-125, (2016)). For tackling hard-to-drug targets and increasing the success in discovering drug molecules, in-depth analysis of drug-target protein interactions performed by biophysical methods will be more and more essential. Here, we review the advantages of NMR spectroscopy as a key technology of biophysical methods and also discuss issues such as using cutting-edge NMR spectrometers and increasing the demand of utilizing conformational dynamics information for promoting small-molecule drug discovery.

Keywords: Conformational analysis; Drug discovery; FBDD; Hit validation; SBDD.

Publication types

• Calorimetry, Differential Scanning
• Crystallography, X-Ray
• Drug Design
• Drug Discovery / methods*
• High-Throughput Screening Assays
• Molecular Docking Simulation
• Nuclear Magnetic Resonance, Biomolecular / methods*
• Protein Binding
• Quantitative Structure-Activity Relationship
• Small Molecule Libraries

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Human PUF60 UHM domain (thioredoxin fusion) in complex with a small molecule binder

• PDB DOI:  https://doi.org/10.2210/pdb6LUR/pdb
• Classification:  SPLICING
• Organism(s):  Escherichia coli K-12 , Homo sapiens
• Expression System:  Escherichia coli
• Mutation(s):  No 
• Deposited:  2020-01-30  Released:  2020-04-29 
• Deposition Author(s):  Takahashi, M. , Hanzawa, H.

Experimental Data Snapshot

• Method:  X-RAY DIFFRACTION
• Resolution:  2.00 Å
• R-Value Free:  0.253 
• R-Value Work:  0.201 
• R-Value Observed:  0.203 

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Revisiting biomolecular NMR spectroscopy for promoting small-molecule drug discovery.

(2020) J Biomol NMR  74 : 501-508

• PubMed :  32306215   Search on PubMed
• DOI:  https://doi.org/10.1007/s10858-020-00314-0
• Primary Citation of Related Structures:   6LUR

Recently, there has been increasing interest in new modalities such as therapeutic antibodies and gene therapy at a number of pharmaceutical companies. Moreover, in small-molecule drug discovery at such companies, efforts have focused on hard-to-drug targets such as inhibiting protein-protein interactions. Biomolecular NMR spectroscopy has been used in drug discovery in a variety of ways, such as for the reliable detection of binding and providing three-dimensional structural information for structure-based drug design. The advantages of using NMR spectroscopy have been known for decades (Jahnke in J Biomol NMR 39:87-90, (2007); Gossert and Jahnke in Prog Nucl Magn Reson Spectrosc 97:82-125, (2016)). For tackling hard-to-drug targets and increasing the success in discovering drug molecules, in-depth analysis of drug-target protein interactions performed by biophysical methods will be more and more essential. Here, we review the advantages of NMR spectroscopy as a key technology of biophysical methods and also discuss issues such as using cutting-edge NMR spectrometers and increasing the demand of utilizing conformational dynamics information for promoting small-molecule drug discovery.

Structure-Based Drug Design Group, Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan. [email protected].

  Explore in 3D :  Structure | Sequence Annotations | Electron Density | Validation Report | Ligand Interaction  (EVU)

Biological assembly 1 assigned by authors and generated by PISA (software)

Macromolecule Content

• Total Structure Weight: 199.63 kDa 
• Atom Count: 13,950 
• Modelled Residue Count: 1,690 
• Deposited Residue Count: 1,776 
• Unique protein chains: 1

Experimental Data

• Space Group:  P 2 1 2 1 2 1

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• Released Date:  2020-04-29 

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• Version 1.0: 2020-04-29 Type: Initial release
• Version 1.1: 2020-05-06 Changes: Database references
• Version 1.2: 2020-12-09 Changes: Database references
• Version 1.3: 2023-11-29 Changes: Data collection, Database references, Refinement description
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NMR as a Tool to Target Protein–Protein Interactions

• First Online: 01 January 2013

Cite this chapter

• Rebecca Del Conte 2 ,
• Daniela Lalli 2 &
• Paola Turano 2  

786 Accesses

NMR spectroscopy plays a dual role in projects aimed at targeting protein–protein interactions (PPIs).While it has been extensively validated as an efficient technique for the initial screening and identification of weakly interacting fragments and for subsequently guiding their optimization into molecules with higher affinity and more favorable drug-like properties, it also represents an extremely powerful tool to monitor the formation of protein–protein complexes in solution and to obtain structural information on these adducts. It allows the identification of the protein interfaces and, in some cases, provides intermolecular distance and orientational restraints that lead to the definition of the relative arrangement of the two proteins. In particular, it constitutes the structural technique of choice for studying weak/ transient protein–protein interactions, which represent the natural targets for drug discovery projects addressing PPIs.

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Del Conte, R., Lalli, D., Turano, P. (2013). NMR as a Tool to Target Protein–Protein Interactions. In: Mangani, S. (eds) Disruption of Protein-Protein Interfaces. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-37999-4_4

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Journal of Biomolecular NMR , 02 Jul 2020 , 74(10-11): 509-519 https://doi.org/10.1007/s10858-020-00330-0   PMID: 32617727 

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