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NMR in the Drug Design

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

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 47885

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Prof. Dr. Simona Golič Grdadolnik

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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

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Keywords

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

Published Papers (10 papers)

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Research

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18 pages, 2775 KiB

Open AccessFeature PaperArticle

On Complex Formation between 5-Fluorouracil and β-Cyclodextrin in Solution and in the Solid State: IR Markers and Detection of Short-Lived Complexes by Diffusion NMR

by Daria L. Melnikova, Zilya F. Badrieva, Mikhail A. Kostin, Corina Maller, Monika Stas, Aneta Buczek, Malgorzata A. Broda, Teobald Kupka, Anne-Marie Kelterer, Peter M. Tolstoy and Vladimir D. Skirda

Molecules 2020, 25(23), 5706; https://doi.org/10.3390/molecules25235706 - 3 Dec 2020

Cited by 15 | Viewed by 3378

Abstract

In this work, the nuclear magnetic resonance (NMR) and IR spectroscopic markers of the complexation between 5-fluorouracil (5-FU) and β-cyclodextrin (β-CD) in solid state and in aqueous solution are investigated. In the attenuated total reflectance(ATR) spectra of 5-FU/β-CD products obtained by physical mixing, kneading and co-precipitation, we have identified the two most promising marker bands that could be used to detect complex formations: the C=O and C-F stretching bands of 5-FU that experience a blue shift by ca. 8 and 2 cm⁻¹ upon complexation. The aqueous solutions were studied by NMR spectroscopy. As routine NMR spectra did not show any signs of complexation, we have analyzed the diffusion attenuation of spin–echo signals and the dependence of the population factor of slowly diffusing components on the diffusion time (diffusion NMR of pulsed-field gradient (PFG) NMR). The analysis has revealed that, at each moment, ~60% of 5-FU molecules form a complex with β-CD and its lifetime is ca. 13.5 ms. It is likely to be an inclusion complex, judging from the independence of the diffusion coefficient of β-CD on complexation. The obtained results could be important for future attempts of finding better methods of targeted anticancer drug delivery. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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15 pages, 3194 KiB

Open AccessArticle

Mimicking the Nucleosomal Context in Peptide-Based Binders of a H3K36me Reader Increases Binding Affinity While Altering the Binding Mode

by Velten Horn, Seino A. K. Jongkees and Hugo van Ingen

Molecules 2020, 25(21), 4951; https://doi.org/10.3390/molecules25214951 - 26 Oct 2020

Viewed by 2184

Abstract

Targeting of proteins in the histone modification machinery has emerged as a promising new direction to fight disease. The search for compounds that inhibit proteins that readout histone modification has led to several new epigenetic drugs, mostly for proteins involved in recognition of acetylated lysines. However, this approach proved to be a challenging task for methyllysine readers, which typically feature shallow binding pockets. Moreover, reader proteins of trimethyllysine K36 on the histone H3 (H3K36me3) not only bind the methyllysine but also the nucleosomal DNA. Here, we sought to find peptide-based binders of H3K36me3 reader PSIP1, which relies on DNA interactions to tightly bind H3K36me3 modified nucleosomes. We designed several peptides that mimic the nucleosomal context of H3K36me3 recognition by including negatively charged Glu-rich regions. Using a detailed NMR analysis, we find that addition of negative charges boosts binding affinity up to 50-fold while decreasing binding to the trimethyllysine binding pocket. Since screening and selection of compounds for reader domains is typically based solely on affinity measurements due to their lack of enzymatic activity, our case highlights the need to carefully control for the binding mode, in particular for the challenging case of H3K36me3 readers. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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18 pages, 3957 KiB

Open AccessArticle

Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains

by Jorden A. Johnson, Noelle M. Olson, Madison J. Tooker, Scott K. Bur and William C.K. Pomerantz

Molecules 2020, 25(17), 3949; https://doi.org/10.3390/molecules25173949 - 29 Aug 2020

Cited by 10 | Viewed by 4927

Abstract

As fragment-based drug discovery has become mainstream, there has been an increase in various screening methodologies. Protein-observed ¹⁹F (PrOF) NMR and ¹H CPMG NMR are two fragment screening assays that have complementary advantages. Here, we sought to combine these two NMR-based assays into a new screening workflow. This combination of protein- and ligand-observed experiments allows for a time- and resource-efficient multiplexed screen of mixtures of fragments and proteins. PrOF NMR is first used to screen mixtures against two proteins. Hit mixtures for each protein are identified then deconvoluted using ¹H CPMG NMR. We demonstrate the benefit of this fragment screening method by conducting the first reported fragment screens against the bromodomains of BPTF and Plasmodium falciparum (Pf) GCN5 using 467 3D-enriched fragments. The hit rates were 6%, 5% and 4% for fragments binding BPTF, PfGCN5, and fragments binding both proteins, respectively. Select hits were characterized, revealing a broad range of affinities from low µM to mM dissociation constants. Follow-up experiments supported a low-affinity second binding site on PfGCN5. This approach can be used to bias fragment screens towards more selective hits at the onset of inhibitor development in a resource- and time-efficient manner. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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15 pages, 1995 KiB

Open AccessArticle

Factors Governing the Chemical Stability and NMR Parameters of Uracil Tautomers and Its 5-Halogen Derivatives

by Kacper Rzepiela, Aneta Buczek, Teobald Kupka and Małgorzata A. Broda

Molecules 2020, 25(17), 3931; https://doi.org/10.3390/molecules25173931 - 28 Aug 2020

Cited by 9 | Viewed by 2785

Abstract

We report on the density functional theory (DFT) modelling of structural, energetic and NMR parameters of uracil and its derivatives (5-halogenouracil (5XU), X = F, Cl, Br and I) in vacuum and in water using the polarizable continuum model (PCM) and the solvent model density (SMD) approach. On the basis of the obtained results, we conclude that the intramolecular electrostatic interactions are the main factors governing the stability of the six tautomeric forms of uracil and 5XU. Two indices of aromaticity, the harmonic oscillator model of aromaticity (HOMA), satisfying the geometric criterion, and the nuclear independent chemical shift (NICS), were applied to evaluate the aromaticity of uracil and its derivatives in the gas phase and water. The values of these parameters showed that the most stable tautomer is the least aromatic. A good performance of newly designed xOPBE density functional in combination with both large aug-cc-pVQZ and small STO(1M)−3G basis sets for predicting chemical shifts of uracil and 5-fluorouracil in vacuum and water was observed. As a practical alternative for calculating the chemical shifts of challenging heterocyclic compounds, we also propose B3LYP calculations with small STO(1M)−3G basis set. The indirect spin–spin coupling constants predicted by B3LYP/aug-cc-pVQZ(mixed) method reproduce the experimental data for uracil and 5-fluorouracil well. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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14 pages, 2653 KiB

Open AccessArticle

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine

by Laura Del Coco, Maria Majellaro, Angelina Boccarelli, Saverio Cellamare, Cosimo Damiano Altomare and Francesco Paolo Fanizzi

Molecules 2020, 25(15), 3502; https://doi.org/10.3390/molecules25153502 - 31 Jul 2020

Cited by 10 | Viewed by 2670

Abstract

A ¹H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC₅₀ value, were investigated, with respect to the controls (K), by the ¹H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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16 pages, 1984 KiB

Open AccessArticle

Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions

by Bogdan Musielak, Weronika Janczyk, Ismael Rodriguez, Jacek Plewka, Dominik Sala, Katarzyna Magiera-Mularz and Tad Holak

Molecules 2020, 25(13), 3017; https://doi.org/10.3390/molecules25133017 - 1 Jul 2020

Cited by 14 | Viewed by 3785

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 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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21 pages, 7572 KiB

Open AccessReview

Applications of Solution NMR in Drug Discovery

by Li Shi and Naixia Zhang

Molecules 2021, 26(3), 576; https://doi.org/10.3390/molecules26030576 - 22 Jan 2021

Cited by 12 | Viewed by 6853

Abstract

During the past decades, solution nuclear magnetic resonance (NMR) spectroscopy has demonstrated itself as a promising tool in drug discovery. Especially, fragment-based drug discovery (FBDD) has benefited a lot from the NMR development. Multiple candidate compounds and FDA-approved drugs derived from FBDD have been developed with the assistance of NMR techniques. NMR has broad applications in different stages of the FBDD process, which includes fragment library construction, hit generation and validation, hit-to-lead optimization and working mechanism elucidation, etc. In this manuscript, we reviewed the current progresses of NMR applications in fragment-based drug discovery, which were illustrated by multiple reported cases. Moreover, the NMR applications in protein-protein interaction (PPI) modulators development and the progress of in-cell NMR for drug discovery were also briefly summarized. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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15 pages, 2546 KiB

Open AccessReview

On the Rational Drug Design for Hypertension through NMR Spectroscopy

by Eleni Chontzopoulou, Andreas G. Tzakos and Thomas Mavromoustakos

Molecules 2021, 26(1), 12; https://doi.org/10.3390/molecules26010012 - 22 Dec 2020

Cited by 3 | Viewed by 3281

Abstract

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state ¹³CP/MAS, ³¹P and ²H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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63 pages, 16854 KiB

Open AccessReview

NMR as a “Gold Standard” Method in Drug Design and Discovery

by Abdul-Hamid Emwas, Kacper Szczepski, Benjamin Gabriel Poulson, Kousik Chandra, Ryan T. McKay, Manel Dhahri, Fatimah Alahmari, Lukasz Jaremko, Joanna Izabela Lachowicz and Mariusz Jaremko

Molecules 2020, 25(20), 4597; https://doi.org/10.3390/molecules25204597 - 9 Oct 2020

Cited by 45 | Viewed by 9915

Abstract

Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still a major challenge because pathogens rapidly and continually evolve developing drug resistance. Cancer cells also change genetically, and current therapeutic techniques may be (or may become) ineffective in many cases. The pathology of many neurological diseases remains an enigma, and the exact etiology and underlying mechanisms are still largely unknown. Viral infections spread and develop much more quickly than does the corresponding research needed to prevent and combat these infections; the present and most relevant outbreak of SARS-CoV-2, which originated in Wuhan, China, illustrates the critical and immediate need to improve drug design and development techniques. Modern day drug discovery is a time-consuming, expensive process. Each new drug takes in excess of 10 years to develop and costs on average more than a billion US dollars. This demonstrates the need of a complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played a critical role in drug discovery ever since its introduction several decades ago. In just three decades, NMR has become a “gold standard” platform technology in medical and pharmacology studies. In this review, we present the major applications of NMR spectroscopy in medical drug discovery and development. The basic concepts, theories, and applications of the most commonly used NMR techniques are presented. We also summarize the advantages and limitations of the primary NMR methods in drug development. Full article

(This article belongs to the Special Issue NMR in the Drug Design)

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18 pages, 3648 KiB

Open AccessReview

A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery

by Qingxin Li and CongBao Kang

Molecules 2020, 25(13), 2974; https://doi.org/10.3390/molecules25132974 - 28 Jun 2020

Cited by 14 | Viewed by 6748

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 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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