NMR Methods to Characterize Protein-Ligand Interactions

Maity, Sanhita; Gundampati, Ravi Kumar; Kumar, Thallapuranam Krishnaswamy Suresh

doi:10.1177/1934578x19849296

Cited by 35 publications

(36 citation statements)

References 77 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Peaks corresponding to acidic protons (‒OH or ‒NH) of remdesivir from F9, a leucine-based formulation, became broader than those from the other formulations without leucine, and shifted downfield. These wider peaks result from inter-molecular interactions [ 55 ]. A peak shift in NMR spectra indicates magnetic field changes.…”

Section: Discussionmentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for emergency use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF< 5 µm; 0.82 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one month of storage at 25 °C/60% relative humidity. An in vivo pharmacokinetic evaluation showed that TFF remdesivir–leucine was poorly absorbed into systemic circulation while TFF remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in the lung, and levels of GS-441524 were greater in the lung with leucine formulation compared to Captisol®. In conclusion, TFF technology produces high-potency remdesivir dry powder formulations for inhalation that are suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Peaks corresponding to acidic protons (--OH or --NH) of remdesivir from F9, a leucine-based formulation, became broader than those from the other formulations without leucine, and shifted downfield. These wider peaks result from inter-molecular interactions [50]. A peak shift in NMR spectra indicates magnetic field changes.…”

Section: Remdesivir In Tff Powder Compositions Can Be Dissolved Absomentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Preprint

View full text Add to dashboard Cite

Remdesivir, an investigational broad-spectrum antiviral agent, has shown in vitro activity against SARS-CoV-2. To maximize direct delivery to the target site, the lungs, we aim to develop remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces a brittle matrix of nanostructured aggregates that can be sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients (e.g. Captisol®, mannitol, lactose, leucine) exhibited suitable aerosol performance (up to 92.4% FPF and 0.86 µm MMAD). Remdesivir was amorphous after the TFF process, which we hypothesize will provide a benefit for drug dissolution once administered to the lungs. Neither the organic/water processing cosolvent or the rapid freezing rate used during the TFF process affected the chemical stability of remdesivir during processing. In conclusion, TFF is a suitable technology for producing remdesivir dry powder formulations suitable for pulmonary administration.

show abstract

“…Various experiments are powerful for probing protein-ligand binding for NMR, while only one measurement is made for other biophysical methods [5,49]. Both ligand-observed and protein-observed experiments are available for determining protein and ligand interactions [4,5,[49][50][51][52][53]. Second, studies are conducted in solutions that are close to physiological conditions and do not require special resins or columns for attaching samples.…”

Section: Advantages Of Nmr In Drug Discoverymentioning

confidence: 99%

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

Li¹,

Kang

2020

Molecules

View full text Add to dashboard Cite

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.

show abstract

NMR Methods to Characterize Protein-Ligand Interactions

Cited by 35 publications

References 77 publications

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

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

Contact Info

Product

Resources

About