Recent Advances in NMR Diffusion Techniques for Studying Drug Binding

2003 ◽  
Vol 56 (9) ◽  
pp. 855 ◽  
Author(s):  
William S. Price
Keyword(s):  
Drug Development ◽  
Study Drug ◽  
Drug Binding ◽  
Model Systems ◽  
Aqueous Samples ◽  
Recent Advances ◽  
Physiological Relevance ◽  
Nmr Diffusion

Characterizing the binding of ligands to macromolecular receptors in solution is important to many areas of chemistry, biology, and nanobiotechnology, but perhaps most notably to drug development. NMR has proven to be particularly useful for such studies, but the systems studied have generally been restricted to model systems with dubious physiological relevance. This paper reviews the use of NMR diffusion measurements to study drug binding and two recent advances that enable measurements to be conducted in more sensitive higher-field NMR spectrometers in non-deuterated aqueous samples.

scholarly journals Antifungal Activities of Antineoplastic Agents:Saccharomyces cerevisiae as a Model System To Study Drug Action

1999 ◽  
Vol 12 (4) ◽  
pp. 583-611 ◽  
Author(s):  
Maria E. Cardenas ◽  
M. Cristina Cruz ◽  
Maurizio Del Poeta ◽  
Namjin Chung ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Genetic Model ◽  
Fungal Infections ◽  
Study Drug ◽  
Drug Action ◽  
Mechanisms Of Action ◽  
Model Systems ◽  
Screening Tools ◽  
Sphingolipid Metabolism

SUMMARY Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells. While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products inhibit target proteins conserved from microorganisms to humans. These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells. In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.

scholarly journals Recent advances in intravenous anesthesia and anesthetics

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 470 ◽  
Author(s):  
Mohamed Mahmoud ◽  
Keira P. Mason
Keyword(s):  
Drug Development ◽  
Delivery Systems ◽  
Intravenous Anesthesia ◽  
Recent Advances ◽  
Soft Drug

Anesthesiology, as a field, has made promising advances in the discovery of novel, safe, effective, and efficient methods to deliver care. This review explores refinement in the technology of soft drug development, unique anesthetic delivery systems, and recent drug and device failures.

Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium

2002 ◽  
Vol 227 (9) ◽  
pp. 724-752 ◽  
Author(s):  
Corrine Welt ◽  
Yisrael Sidis ◽  
Henry Keutmann ◽  
Alan Schneyer
Keyword(s):  
Hormone Secretion ◽  
Signal Propagation ◽  
Cellular Level ◽  
Model Systems ◽  
Pituitary Hormone ◽  
New Paradigm ◽  
Activin Signaling ◽  
Physiological Relevance ◽  
Paracrine Growth Factor

It has been 70 years since the name inhibin was used to describe a gonadal factor that negatively regulated pituitary hormone secretion. The majority of this period was required to achieve purification and definitive characterization of inhibin, an event closely followed by identification and characterization of activin and follistatin (FS). In contrast, the last 15–20 years saw a virtual explosion of information regarding the biochemistry, physiology, and biosynthesis of these proteins, as well as identification of activin receptors, and a unique mechanism for FS action—the nearly irreversible binding and neutralization of activin. Many of these discoveries have been previously summarized; therefore, this review will cover the period from the mid 1990s to present, with particular emphasis on emerging themes and recent advances. As the field has matured, recent efforts have focused more on human studies, so the endocrinology of inhibin, activin, and FS in the human is summarized first. Another area receiving significant recent attention is local actions of activin and its regulation by both FS and inhibin. Because activin and FS are produced in many tissues, we chose to focus on a few particular examples with the most extensive experimental support, the pituitary and the developing follicle, although nonreproductive actions of activin and FS are also discussed. At the cellular level, it now seems that activin acts largely as an autocrine and/or paracrine growth factor, similar to other members of the transforming growh factor β superfamily. As we discuss in the next section, its actions are regulated extracellularly by both inhibin and FS. In the final section, intracellular mediators and modulators of activin signaling are reviewed in detail. Many of these are shared with other transforming growh factor β superfamily members as well as unrelated molecules, and in a number of cases, their physiological relevance to activin signal propagation remains to be elucidated. Nevertheless, taken together, recent findings suggest that it may be more appropriate to consider a new paradigm for inhibin, activin, and FS in which activin signaling is regulated extracellularly by both inhibin and FS whereas a number of intracellular proteins act to modulate cellular responses to these activin signals. It is therefore the balance between activin and all of its modulators, rather than the actions of any one component, that determines the final biological outcome. As technology and model systems become more sophisticated in the next few years, it should become possible to test this concept directly to more clearly define the role of activin, inhibin, and FS in reproductive physiology.

scholarly journals Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase

2020 ◽  
Author(s):  
Christian Seitz ◽  
Lorenzo Casalino ◽  
Robert Konecny ◽  
Gary Huber ◽  
Rommie E. Amaro ◽  
...  
Keyword(s):  
Drug Development ◽  
Ligand Binding ◽  
Binding Site ◽  
Brownian Dynamics ◽  
Drug Binding ◽  
Binding Mechanism ◽  
Drug Effectiveness ◽  
Future Drug ◽  
Dynamics Simulations ◽  
Inhibit Antibody

AbstractInfluenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase.Statement of SignificanceThe influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.

Cardiac muscle diseases in genetically engineered mice: evolution of molecular physiology

1995 ◽  
Vol 269 (3) ◽  
pp. H755-H766 ◽  
Author(s):  
K. R. Chien
Keyword(s):  
Cardiac Muscle ◽  
Large Body ◽  
Genetically Engineered ◽  
Mouse Genetics ◽  
Model Systems ◽  
Molecular Physiology ◽  
Muscle Diseases ◽  
Recent Advances ◽  
Genetically Engineered Mice

Recent advances in molecular, cellular, and genetically based technologies now offer the possibility of generating genetically engineered mice that display physiological phenotypes with direct relevance to human pathophysiological states. The ability to create gene ablations, gene duplications, and gene modifications should allow the use of genetic approaches to map in vivo pathways responsible for complex physiological phenotypes. Recent work from our laboratory utilizing this approach to study cardiac muscle diseases in both the adult context (cardiac hypertrophy) and in the embryonic context (congenital ventricular defects) will be discussed, as well as the steps that led to the generation and characterization of these novel mouse model systems. A large body of work from independent laboratories now points to the inception of a new field of molecular physiology that will fuse mouse genetics and in vivo physiology using appropriate miniaturized physiological technology. Recent advances and prospects for future directions are summarized.

scholarly journals Vesicle Size Regulates Nanotube Formation in the Cell

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Qian Peter Su ◽  
Wanqing Du ◽  
Qinghua Ji ◽  
Boxin Xue ◽  
Dong Jiang ◽  
...  
Keyword(s):  
Single Molecule ◽  
Model Systems ◽  
Organelle Biogenesis ◽  
Membrane Deformation ◽  
Vesicle Size ◽  
Cellular Processes ◽  
Vesicle Recycling ◽  
Physiological Relevance

Abstract Intracellular membrane nanotube formation and its dynamics play important roles for cargo transportation and organelle biogenesis. Regarding the regulation mechanisms, while much attention has been paid on the lipid composition and its associated protein molecules, effects of the vesicle size has not been studied in the cell. Giant unilamellar vesicles (GUVs) are often used for in vitro membrane deformation studies, but they are much larger than most intracellular vesicles and the in vitro studies also lack physiological relevance. Here, we use lysosomes and autolysosomes, whose sizes range between 100 nm and 1 μm, as model systems to study the size effects on nanotube formation both in vivo and in vitro. Single molecule observations indicate that driven by kinesin motors, small vesicles (100–200 nm) are mainly transported along the tracks while a remarkable portion of large vesicles (500–1000 nm) form nanotubes. This size effect is further confirmed by in vitro reconstitution assays on liposomes and purified lysosomes and autolysosomes. We also apply Atomic Force Microscopy (AFM) to measure the initiation force for nanotube formation. These results suggest that the size-dependence may be one of the mechanisms for cells to regulate cellular processes involving membrane-deformation, such as the timing of tubulation-mediated vesicle recycling.

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