Biophysical screening in fragment-based drug design: a brief overview

Robson-Tull, Jacob

doi:10.1093/biohorizons/hzy015

Cited by 18 publications

(24 citation statements)

References 69 publications

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“…Unlike traditional HTS, which can survey a large number of molecules ranging from a few hundred thousand to a few million [ 209 ], FBDD usually surveys a few thousand molecules (~1000–15000) from libraries with greater chemical diversity [ 209 , 210 ]. FBDD is a main-stream screening technique for drug discovery [ 207 , 209 , 211 , 212 , 213 , 214 , 215 , 216 ] and NMR is standard for many FBDD studies [ 209 ]. Additional methods and techniques such as SPR, X-ray crystallography [ 209 , 217 , 218 , 219 , 220 ] etc.…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“…FBDD is a main-stream screening technique for drug discovery [ 207 , 209 , 211 , 212 , 213 , 214 , 215 , 216 ] and NMR is standard for many FBDD studies [ 209 ]. Additional methods and techniques such as SPR, X-ray crystallography [ 209 , 217 , 218 , 219 , 220 ] etc. have also been used in FBDD studies, accompanied or unaccompanied by NMR experiments.…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“…Water-Ligand Observed through Gradient Spectroscopy (WaterLOGSY) is a second type of STD (see Figure 9 b). The main difference with normal STD NMR is that water is the saturated signal [ 261 ], and instead of observing lower peak intensities, peak inversions indicate the presence of ligand binding [ 209 ].…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“… Illustration of STD NMR ( a ) and WaterLOGSY ( b ) in drug design. Copied with permission from Robson-Tull [ 209 ]. …”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

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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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Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“… Illustration of STD NMR ( a ) and WaterLOGSY ( b ) in drug design. Copied with permission from Robson-Tull [ 209 ]. …”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

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

et al. 2020

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“…In the case of the experimental approaches, the fragments are validated by some screening methods some of which are high throughput, e.g. by surface plasmon resonance (10). This is a critical step in the process of fragment-based design (FBD).…”

Section: Introductionmentioning

confidence: 99%

MCSS-based Predictions of Binding Mode and Selectivity of Nucleotide Ligands

González-Alemán

Chevrollier

Simões³

et al. 2019

Preprint

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Computational fragment-based approaches have been widely used in drug design and drug discovery. One of the limitations for their application is the lack of performance of the scoring functions. With the emergence of new fragment-based approaches for single-stranded RNA ligands, we propose an analysis of the docking power of an MCSS-based approach evaluated on nucleotide binding sites. Combined with a clustering of MCSS-generated poses and some state-of-the-art scoring functions, the results suggest that it could be used in the design of oligonucleotides. MCSS | ligand binding | docking | scoring | protein-nucleotide interactions | FBDCorrespondence: fabrice.leclerc@i2bc.paris-saclay.fr

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Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition**

Vaaltyn

Mateos-Jimenez²,

Müller

et al. 2022

ChemBioChem

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Contemporary medicinal chemistry considers fragment-based drug discovery (FBDD) and inhibition of protein-protein interactions (PPI) as important means of expanding the volume of druggable chemical space. However, the ability to robustly identify valid fragments and PPI inhibitors is an enormous challenge, requiring the application of sensitive biophysical methodology. Accordingly, in this study, we exploited the speed and sensitivity of nanoelectrospray (nano-ESI) native mass spectrometry to identify a small collection of fragments which bind to the TPR2AB domain of HOP. Follow-up biophysical assessment of a small selection of binding fragments confirmed binding to the single TPR2A domain, and that this binding translated into PPI inhibitory activity between TPR2A and the HSP90 C-terminal domain. An in-silico assessment of binding fragments at the PPI interfacial region, provided valuable structural insight for future fragment elaboration strategies, including the identification of losartan as a weak, albeit dose-dependent inhibitor of the target PPI.

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Biophysical screening in fragment-based drug design: a brief overview

Cited by 18 publications

References 69 publications

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

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

MCSS-based Predictions of Binding Mode and Selectivity of Nucleotide Ligands

Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition**

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