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Special Issue "NMR in the Drug Design"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 September 2020.

Special Issue Editor

Prof. Dr. Simona Golič Grdadolnik
Website
Guest Editor
Laboratory for Molecular Structural Dynamics, National Institute of Chemistry Hajdrihova 19, SI-1000 Ljubljana, Slovenia
Interests: NMR spectroscopy; ligand–protein interactions; dynamic processes; molecular dynamics simulations; drug design

Special Issue Information

Dear Colleagues,

NMR spectroscopy has been widely applied in the early stages of drug discovery. It is especially suited to the structure-based approach in lead design strategies, as it is the most powerful method for studies of structure, dynamics, and the interaction of molecules in solution. With the development of cryogenic NMR probe technology, it has also become a high-throughput screening method, which is particularly powerful for the identification of the binding of low-affinity, low-molecular-mass fragments in fragment-based drug design. It is argued that in structure-based design, too many expectations has been placed on rigid molecular structures. Indeed, molecules are inherently flexible systems. Drug targets like proteins can undergo functionally relevant conformational transitions on a wide range of scales in time and space. Motions between thermally accessible protein conformational states can modify ligand binding sites, producing distinct chemical interactions between the ligand and the protein and thus affecting the ligand biological profile. The ligands possessing the potential for the development of new therapeutic agents are usually molecules of low-molecular weight with differing intrinsic flexibilities that can affect their binding interactions with drug targets. A great advantage of NMR spectroscopy is its ability to monitor and discriminate dynamic events on a broad range of time scales from fast (< ns) to slow (ms-s) internal motions without perturbing chemical and structural equilibria. Thus, NMR spectroscopy can provide atomic resolution insight with regard to both molecular structure and dynamics. Such combined structure-dynamic insight can improve the efficiency of structure-based design and accelerate the discovery of novel drugs.

The aim of this Special Issue is to attract contributions on all aspects of the application of NMR spectroscopy in the design and discovery of drug candidates, with special emphasis on the NMR studies addressing molecular flexibilities in relation to the biological profile of drug candidates or the druggability of targets.

Prof. Dr. Simona Golič Grdadolnik
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ligand-based NMR
  • Protein (target)-based NMR
  • NMR screening
  • Ligand-target interactions
  • Molecular flexibility.

Published Papers (2 papers)

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Research

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Open AccessArticle
Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions
Molecules 2020, 25(13), 3017; https://doi.org/10.3390/molecules25133017 - 01 Jul 2020
Abstract
Screening for small-molecule fragments that can lead to potent inhibitors of protein–protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM–mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist [...] Read more.
Screening for small-molecule fragments that can lead to potent inhibitors of protein–protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM–mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak μM–mM ligand–protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex’s protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers. Full article
(This article belongs to the Special Issue NMR in the Drug Design)
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Review

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Open AccessReview
A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery
Molecules 2020, 25(13), 2974; https://doi.org/10.3390/molecules25132974 - 28 Jun 2020
Abstract
Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps [...] Read more.
Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps as hit identification and lead optimization. NMR is frequently used to locate ligand-binding sites on a target protein and to determine ligand binding modes. NMR spectroscopy is also a unique tool in fragment-based drug design (FBDD), as it is able to investigate target-ligand interactions with diverse binding affinities. NMR spectroscopy is able to identify fragments that bind weakly to a target, making it valuable for identifying hits targeting undruggable sites. In this review, we summarize the roles of solution NMR spectroscopy in drug discovery. We describe some methods that are used in identifying fragments, understanding the mechanism of action for a ligand, and monitoring the conformational changes of a target induced by ligand binding. A number of studies have proven that 19F-NMR is very powerful in screening fragments and detecting protein conformational changes. In-cell NMR will also play important roles in drug discovery by elucidating protein-ligand interactions in living cells. Full article
(This article belongs to the Special Issue NMR in the Drug Design)
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