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Solution NMR Spectroscopy in the Early Stage of Target-Based Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 12681

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Dr. Congbao Kang

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Guest Editor

Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore
Interests: drug discovery; NMR spectroscopy; structural biology; fragment-based drug design; target-ligand interactions; membrane proteins
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Special Issue Information

Dear Colleagues,

Structure-based drug design is a powerful strategy in drug discovery, while knowing the structures of the targets and their complexes with developed compounds is indispensable. Despite some challenges, solution NMR spectroscopy plays important roles in determining the structures and dynamics of a protein and its complexes, meaning that NMR spectroscopy plays an important role in target-based drug discovery. Fragment-based drug design is an economic and efficient strategy to develop drug compounds, which has been widely used in target-based drug discovery projects. Several drug derived from fragments have been approved and entered into clinical studies. As NMR is able to determine weak bindings (affinity in µM to mM), several experiments, such as ¹⁹F-NMR, STD-NMR, ¹H-¹⁵N-HSQC, and WaterLOGSY, have been used in fragment screening.

This Special Issue covers the application of solution NMR spectroscopy in the early stage of target-based drug discovery, which usually consists of steps of hit screening, hit conformation, hit to lead, and lead optimization. Papers related to the structural determination of a macromolecule, molecular interactions between a protein and compound, NMR in fragment-based drug discovery, and others related to drug discovery, will be considered for this Special Issue.

Dr. Congbao Kang
Guest Editor

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Published Papers (4 papers)

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Research

10 pages, 11941 KiB

Open AccessArticle

Secondary Structures of the Transmembrane Domain of SARS-CoV-2 Spike Protein in Detergent Micelles

by Qingxin Li, Qiwei Huang and Congbao Kang

Int. J. Mol. Sci. 2022, 23(3), 1040; https://doi.org/10.3390/ijms23031040 - 18 Jan 2022

Cited by 5 | Viewed by 2456

Abstract

Spike protein of SARS-CoV-2 contains a single-span transmembrane (TM) domain and plays roles in receptor binding, viral attachment and viral entry to the host cells. The TM domain of spike protein is critical for viral infectivity. Herein, the TM domain of spike protein of SARS-CoV-2 was reconstituted in detergent micelles and subjected to structural analysis using solution NMR spectroscopy. The results demonstrate that the TM domain of the protein forms a helical structure in detergent micelles. An unstructured linker is identified between the TM helix and heptapeptide repeat 2 region. The linker is due to the proline residue at position 1213. Side chains of the three tryptophan residues preceding to and within the TM helix important for the function of S-protein might adopt multiple conformations which may be critical for their function. The side chain of W1212 was shown to be exposed to solvent and the side chains of residues W1214 and W1217 are buried in micelles. Relaxation study shows that the TM helix is rigid in solution while several residues have exchanges. The secondary structure and dynamics of the TM domain in this study provide insights into the function of the TM domain of spike protein. Full article

(This article belongs to the Special Issue Solution NMR Spectroscopy in the Early Stage of Target-Based Drug Discovery)

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20 pages, 5662 KiB

Open AccessArticle

Deciphering the Binding Interactions between Acinetobacter baumannii ACP and β-ketoacyl ACP Synthase III to Improve Antibiotic Targeting Using NMR Spectroscopy

by Sungjae Choi, Jungwoo Park, Jiwon Yeon, Ahjin Jang, Woo Cheol Lee and Yangmee Kim

Int. J. Mol. Sci. 2021, 22(7), 3317; https://doi.org/10.3390/ijms22073317 - 24 Mar 2021

Cited by 5 | Viewed by 2346

Abstract

Fatty acid synthesis is essential for bacterial viability. Thus, fatty acid synthases (FASs) represent effective targets for antibiotics. Nevertheless, multidrug-resistant bacteria, including the human opportunistic bacteria, Acinetobacter baumannii, are emerging threats. Meanwhile, the FAS pathway of A. baumannii is relatively unexplored. Considering that acyl carrier protein (ACP) has an important role in the delivery of fatty acyl intermediates to other FAS enzymes, we elucidated the solution structure of A. baumannii ACP (AbACP) and, using NMR spectroscopy, investigated its interactions with β-ketoacyl ACP synthase III (AbKAS III), which initiates fatty acid elongation. The results show that AbACP comprises four helices, while Ca²⁺ reduces the electrostatic repulsion between acid residues, and the unconserved F47 plays a key role in thermal stability. Moreover, AbACP exhibits flexibility near the hydrophobic cavity entrance from D59 to T65, as well as in the α₁α₂ loop region. Further, F29 and A69 participate in slow exchanges, which may be related to shuttling of the growing acyl chain. Additionally, electrostatic interactions occur between the α₂ and α₃-helix of ACP and AbKAS III, while the hydrophobic interactions through the ACP α₂-helix are seemingly important. Our study provides insights for development of potent antibiotics capable of inhibiting A. baumannii FAS protein–protein interactions. Full article

(This article belongs to the Special Issue Solution NMR Spectroscopy in the Early Stage of Target-Based Drug Discovery)

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16 pages, 3487 KiB

Open AccessArticle

NMR-Guided Repositioning of Non-Steroidal Anti-Inflammatory Drugs into Tight Junction Modulators

by Takeshi Tenno, Kohki Kataoka, Natsuko Goda and Hidekazu Hiroaki

Int. J. Mol. Sci. 2021, 22(5), 2583; https://doi.org/10.3390/ijms22052583 - 4 Mar 2021

Cited by 4 | Viewed by 4057

Abstract

Bioavailability is a major bottleneck in the clinical application of medium molecular weight therapeutics, including protein and peptide drugs. Paracellular transport of these molecules is hampered by intercellular tight junction (TJ) complexes. Therefore, safe chemical regulators for TJ loosening are desired. Here, we showed a potential application of select non-steroidal anti-inflammatory drugs (NSAIDs) as TJ modulators. Based on our previous observation that diclofenac and flufenamic acid directly bound various PDZ domains with a broad specificity, we applied solution nuclear magnetic resonance techniques to examine the interaction of other NSAIDs and the first PDZ domain (PDZ1) of zonula occludens (ZO)-1, ZO-1(PDZ1). Inhibition of ZO-1(PDZ1) is expected to provide loosening of the epithelial barrier function because the domain plays a crucial role in maintaining TJ integrity. Accordingly, diclofenac and indomethacin were found to decrease the subcellular localization of claudin (CLD)-2 but not occludin and ZO-1 at the apicolateral intercellular compartment of Madin–Darby canine kidney (MDCK) II cells. These NSAIDs exhibited 125–155% improved paracellular efflux of fluorescein isothiocyanate insulin for the Caco-2 cell monolayer. We propose that these NSAIDs can be repurposed as drug absorption enhancers for peptide drugs. Full article

(This article belongs to the Special Issue Solution NMR Spectroscopy in the Early Stage of Target-Based Drug Discovery)

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13 pages, 1236 KiB

Open AccessArticle

Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I

by Jon Gil-Martínez, Iratxe Macias, Luca Unione, Ganeko Bernardo-Seisdedos, Fernando Lopitz-Otsoa, David Fernandez-Ramos, Ana Lain, Arantza Sanz-Parra, José M Mato and Oscar Millet

Int. J. Mol. Sci. 2021, 22(4), 1789; https://doi.org/10.3390/ijms22041789 - 11 Feb 2021

Cited by 6 | Viewed by 2986

Abstract

Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1. Full article

(This article belongs to the Special Issue Solution NMR Spectroscopy in the Early Stage of Target-Based Drug Discovery)

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