Applications of In-Cell NMR in Structural Biology and Drug Discovery

Kang, CongBao

doi:10.3390/ijms20010139

Cited by 40 publications

(63 citation statements)

References 144 publications

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“…Compared with other methods, NMR screening gives rise to less false positive hits and a mixture of fragments can be screened. A number of NMR experiments have been utilized in FBDD by identifying various hits binding to a specific site on targets ( Gossert and Jahnke, 2016 ; Norton et al, 2016 ; Li and Kang, 2017 ; Sugiki et al, 2018 ; Kang, 2019a , b ). As shown in Table 1 , several methods can be applied in fragment screening.…”

Section: Fragment Screening Methodsmentioning

confidence: 99%

Application of Fragment-Based Drug Discovery to Versatile Targets

2020

Front. Mol. Biosci.

134

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Fragment-based drug discovery (FBDD) is a powerful method to develop potent smallmolecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.

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Section: Fragment Screening Methodsmentioning

confidence: 99%

Application of Fragment-Based Drug Discovery to Versatile Targets

2020

Front. Mol. Biosci.

134

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“…In the target-detected in-cell NMR only the target of interest is isotopically labeled (i.e., 15 N labeled protein). For instance, target proteins can be isotopically labeled during cell growth in isotopically enriched ( 13 C, 15 N, or both 15 N/ 13 C) media [ 410 ]. The cell type and the labeling method may vary across experiments.…”

Section: In-cell Nmr Approachesmentioning

confidence: 99%

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

et al. 2020

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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.

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“…There are a few biophysical and biochemical methods, such as cellular thermal shift assay [153,154] and polarized microscopy [155], that have been adopted in target engagement. Solution NMR spectroscopy might play a role in target engagement by probing protein and ligand interactions in living cells [156].…”

Section: Target Engagementmentioning

confidence: 99%

“…Suitable expression vectors (highlighted in green) should be selected for target protein expression. Proteins can also be purified in vitro and transformed/injected into cells using various methods [63,156,169]. The outcome of in-cell NMR is listed in the figure.…”

Section: Target Engagementmentioning

confidence: 99%

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

Li¹,

Kang

2020

Molecules

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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.

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Applications of In-Cell NMR in Structural Biology and Drug Discovery

Cited by 40 publications

References 144 publications

Application of Fragment-Based Drug Discovery to Versatile Targets

Application of Fragment-Based Drug Discovery to Versatile Targets

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

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

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