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NMR Spectroscopy in Drug Discovery Research

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 6602

Special Issue Editor

Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Pietro Castellino 111, 80131 Naples, Italy
Interests: structural biology; NMR; drug discovery; conformational analysis of proteins and peptides; protein–protein interactions (PPIs); design and evaluation of PPI inhibitors; structure-based drug design; molecular modeling; docking; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

NMR spectroscopy is an ideal technique to study target–ligand interactions that are at the basis of drug discovery research. Due to tremendous improvements, affecting both hardware and methodologies, including the introduction of fast NMR data acquisition, novel NMR screening routes for fragment-based drug discovery and development (FBDD) have been set up to identify small molecules binding to a specific target. During the past decade, FBDD has been applied to discover original ligands of various drug targets such as DNA, RNA, enzymes, membrane proteins, as well as intrinsically disordered proteins, thus proving itself as a promising drug discovery strategy. Fragment linking approaches for structure-based drug discovery, i.e., chemical linking of binding fragments, based on the knowledge of the structural details characterizing the target binding pocket, represent rational routes to generate new compounds interacting with higher affinity and selectivity with the chosen target.

A part from the traditional target-focused drug discovery, targeting protein–protein interactions (PPIs) is another interesting approach for drug development. Being the surface areas involved in protein–protein interactions often large and flat, peptides and peptidomimetics are ideal candidates to generate effective PPI modulators, as they can mimic the structural features of complex PPI interfaces. Techniques for the preparation of large NMR-oriented peptide libraries and original strategies for NMR-based drug development based on peptides have been established.

Nevertheless, the introduction of solid-state biomolecular NMR techniques has also made possible to observe drugs and ligands at their sites of action in membrane proteins. Another interesting aspect is that, similar to the in vitro NMR applications in drug development, NMR-based methods can also be employed to study target–compound interactions in living cells. In-cell NMR has already been implemented for compound screening and target engagement.

This Special Issue will be centered on the above presented topics and looks for contributions (communications, full papers, and reviews) related to the latest trends in NMR-based drug discovery research. In detail, this Special Issue intends to collect studies related to the development of novel NMR methods for screening libraries of compounds and investigating target–ligand interactions and more application-oriented works concerning with NMR-driven identification of compounds targeting specific targets or protein–protein interactions. Works conducted by integrating NMR data with those from other experimental techniques along with computational tools are highly welcome.

Dr. Marilisa Leone
Guest Editor

Manuscript Submission Information

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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 2700 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

  • Solution state NMR
  • In cell NMR
  • Solid state NMR
  • NMR screening
  • Fragment-based drug discovery
  • SAR by NMR
  • Ligand-based approaches
  • Target-based approaches
  • Protein–ligand interactions
  • Peptides as drugs
  • Epitope mapping

Published Papers (4 papers)

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Research

12 pages, 1303 KiB  
Article
Drugging the Undruggable Trypanosoma brucei Monothiol Glutaredoxin 1
by Annagiulia Favaro, Giovanni Bolcato, Marcelo A. Comini, Stefano Moro, Massimo Bellanda and Mattia Sturlese
Molecules 2023, 28(3), 1276; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031276 - 28 Jan 2023
Cited by 1 | Viewed by 1258
Abstract
Trypanosoma brucei is a species of kinetoplastid causing sleeping sickness in humans and nagana in cows and horses. One of the peculiarities of this species of parasites is represented by their redox metabolism. One of the proteins involved in this redox machinery is [...] Read more.
Trypanosoma brucei is a species of kinetoplastid causing sleeping sickness in humans and nagana in cows and horses. One of the peculiarities of this species of parasites is represented by their redox metabolism. One of the proteins involved in this redox machinery is the monothiol glutaredoxin 1 (1CGrx1) which is characterized by a unique disordered N-terminal extension exclusively conserved in trypanosomatids and other organisms. This region modulates the binding profile of the glutathione/trypanothione binding site, one of the functional regions of 1CGrx1. No endogenous ligands are known to bind this protein which does not present well-shaped binding sites, making it target particularly challenging to target. With the aim of targeting this peculiar system, we carried out two different screenings: (i) a fragment-based lead discovery campaign directed to the N-terminal as well as to the canonical binding site of 1CGrx1; (ii) a structure-based virtual screening directed to the 1CGrx1 canonical binding site. Here we report a small molecule that binds at the glutathione binding site in which the binding mode of the molecule was deeply investigated by Nuclear Magnetic Resonance (NMR). This compound represents an important step in the attempt to develop a novel strategy to interfere with the peculiar Trypanosoma Brucei redox system, making it possible to shed light on the perturbation of this biochemical machinery and eventually to novel therapeutic possibilities. Full article
(This article belongs to the Special Issue NMR Spectroscopy in Drug Discovery Research)
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21 pages, 5633 KiB  
Article
Insight on the Interaction between the Camptothecin Derivative and DNA Oligomer Mimicking the Target of Topo I Inhibitors
by Wojciech Bocian, Beata Naumczuk, Magdalena Urbanowicz, Jerzy Sitkowski, Elżbieta Bednarek, Katarzyna Wiktorska, Anna Pogorzelska, Ewelina Wielgus and Lech Kozerski
Molecules 2022, 27(20), 6946; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27206946 - 17 Oct 2022
Cited by 4 | Viewed by 1333
Abstract
The understanding of the mechanism of Topo I inhibition by organic ligands is a crucial source of information that has led to the design of more effective and safe pharmaceuticals in oncological chemotherapy. The vast number of inhibitors that have been studied in [...] Read more.
The understanding of the mechanism of Topo I inhibition by organic ligands is a crucial source of information that has led to the design of more effective and safe pharmaceuticals in oncological chemotherapy. The vast number of inhibitors that have been studied in this respect over the last decades have enabled the creation of a concept of an ‘interfacial inhibitor’, thereby describing the machinery of Topo I inhibition. The central module of action of this machinery is the interface of a Topo I/DNA/inhibitor ternary complex. Most of the ‘interfacial inhibitors’ are primarily kinetic inhibitors that form molecular complexes with an “on–off” rate timing; therefore, all of the contacts between the inhibitor and both the enzyme and the DNA are essential to keep the complex stable and reduce the “off rate”. To test this hypothesis, we designed the compound using a C-9-(N-(2′-hydroxyethyl)amino)methyl substituent in an SN38 core, with a view that a flexible substituent may bind inside the nick of a model of the DNA and stabilize the complex, leading to a reduction in the “off rate” of a ligand in a potential ternary complex in vivo. Using docking analysis and molecular dynamics, free energy calculations on the level of the MM-PBSA and MM-GBSA model, here we presented the in silico-calculated structure of a ternary complex involving the studied compound 1. This confirmed our suggestion that compound 1 is situated in a groove of the nicked DNA model in a few conformations. The number of hydrogen bonds between the components of a ternary complex was established, which strengthens the complex and supports our view. The docking analysis and free energy calculations for the receptor structures which were obtained in the MD simulations of the ternary complex 1/DNA/Topo I show that the binding constant is stronger than it was for similar complexes with TPT, CPT, and SN38, which are commonly considered as strong Topo I inhibitors. The binary complex structure 1/DNA was calculated and compared with the experimental results of a complex that was in a solution. The analysis of the cross-peaks in NOESY spectra allowed us to assign the dipolar interactions between the given protons in the calculated structures. A DOSY experiment in the solution confirmed the strong binding of a ligand in a binary complex, having a Ka of 746 mM−1, which was compared with a Ka of 3.78 mM−1 for TPT. The MALDI-ToF MS showed the presence of the biohybrid, thus evidencing the occurrence of DNA alkylation by compound 1. Because of it having a strong molecular complex, alkylation is the most efficient way to reduce the “on–off” timing as it acts as a tool that causes the cog to brake in a working gear, and this is this activity we want to highlight in our contribution. Finally, the Topo I inhibition test showed a lower IC50 of the studied compound than it did for CPT and SN38. Full article
(This article belongs to the Special Issue NMR Spectroscopy in Drug Discovery Research)
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20 pages, 3407 KiB  
Article
Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells
by Caroline Delehedde, Marcel Culcasi, Emilie Ricquebourg, Mathieu Cassien, Didier Siri, Bruno Blaive, Sylvia Pietri and Sophie Thétiot-Laurent
Molecules 2022, 27(14), 4506; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144506 - 14 Jul 2022
Cited by 3 | Viewed by 1490
Abstract
In order to discover new 31P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in [...] Read more.
In order to discover new 31P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pKas (ranging 6.28–6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδab between the acidic and basic forms) ranging from 9.2–10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pKas and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδab. Finally, the hit 31P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pKa = 6.45 with Δδab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units. Full article
(This article belongs to the Special Issue NMR Spectroscopy in Drug Discovery Research)
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14 pages, 3474 KiB  
Article
Acid–Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis
by Michał Kosno, Tomasz Laskowski, Joanna E. Frackowiak, Agnieszka Potęga, Agnieszka Kurdyn, Witold Andrałojć, Julia Borzyszkowska-Bukowska, Katarzyna Szwarc-Karabyka and Zofia Mazerska
Molecules 2022, 27(13), 3995; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27133995 - 21 Jun 2022
Cited by 5 | Viewed by 1280
Abstract
Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected [...] Read more.
Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic transformations in vitro and in tumor cells. However, the physicochemical properties of UAs, which could possibly affect their interactions with molecular targets, remain unknown. Therefore, we selected four highly active UAs for the assessment of physicochemical parameters under various pH conditions. We determined the compounds’ pKa dissociation constants as well as their potential to self-associate. Both parameters were determined by detailed and complex chemometric analysis of UV-Vis spectra supported by nuclear magnetic resonance (NMR) spectroscopy. The obtained results indicate that general molecular properties of UAs in aqueous media, including their protonation state, self-association ratio, and solubility, are strongly pH-dependent, particularly in the physiological pH range of 6 to 8. In conclusion, we describe the detailed physicochemical characteristics of UAs, which might contribute to their selectivity towards tumour cells as opposed to their effect on normal cells. Full article
(This article belongs to the Special Issue NMR Spectroscopy in Drug Discovery Research)
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