scholarly journals Licofelone-DPPC Interactions: Putting Membrane Lipids on the Radar of Drug Development

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 516 ◽  
Author(s):  
Catarina Pereira-Leite ◽  
Daniela Lopes-de-Campos ◽  
Philippe Fontaine ◽  
Iolanda Cuccovia ◽  
Cláudia Nunes ◽  
...  
Keyword(s):  
Drug Development ◽  
Membrane Lipids ◽  
Grazing Incidence ◽  
Drug Candidate ◽  
Local Order ◽  
Lipid Phase ◽  
Brewster Angle Microscopy ◽  
Pharmacological Characterization ◽  
Additional Information ◽  
Preclinical Phase

(1) Background: Membrane lipids have been disregarded in drug development throughout the years. Recently, they gained attention in drug design as targets, but they are still disregarded in the latter stages. Thus, this study aims to highlight the relevance of considering membrane lipids in the preclinical phase of drug development. (2) Methods: The interactions of a drug candidate for clinical use (licofelone) with a membrane model system made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated by combining Langmuir isotherms, Brewster angle microscopy (BAM), polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and grazing-incidence X-ray diffraction (GIXD) measurements. (3) Results: Licofelone caused the expansion of the DPPC isotherm without changing the lipid phase transition profile. Moreover, licofelone induced the reduction of DPPC packing density, while increasing the local order of the DPPC acyl chains. (4) Conclusions: The licofelone-induced alterations in the structural organization of phosphatidylcholine monolayers may be related to its pharmacological actions. Thus, the combination of studying drug-membrane interactions with the pharmacological characterization that occurs in the preclinical stage may gather additional information about the mechanisms of action and toxicity of drug candidates. Ultimately, the addition of this innovative step shall improve the success rate of drug development.

scholarly journals Has molecular imaging delivered to drug development?

2017 ◽  
Vol 375 (2107) ◽  
pp. 20170112 ◽  
Author(s):  
Philip S. Murphy ◽  
Neel Patel ◽  
Timothy J. McCarthy
Keyword(s):  
Molecular Imaging ◽  
Drug Development ◽  
Clinical Studies ◽  
Pharmaceutical Research ◽  
Whole Body ◽  
Drug Candidate ◽  
Clinical Drug Development ◽  
Target Binding ◽  
The Brain ◽  
Clinical Drug

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.

scholarly journals Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

2021 ◽  
Vol 11 ◽  
Author(s):  
Tong Zhu
Keyword(s):  
Drug Development ◽  
Drug Exposure ◽  
Phase 1 ◽  
Drug Candidate ◽  
Phase 2 ◽  
Medical Needs ◽  
Clinical Drug Development ◽  
Human Pharmacology ◽  
Exposure Target ◽  
Target Binding

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

Properties of β-sitostanol/DPPC monolayers studied with Grazing Incidence X-ray Diffraction (GIXD) and Brewster Angle Microscopy

2011 ◽  
Vol 364 (1) ◽  
pp. 133-139 ◽  
Author(s):  
Katarzyna Hąc-Wydro ◽  
Michał Flasiński ◽  
Marcin Broniatowski ◽  
Patrycja Dynarowicz-Łątka ◽  
Jarosław Majewski
Keyword(s):  
Grazing Incidence ◽  
Brewster Angle ◽  
Brewster Angle Microscopy ◽  
X Ray Diffraction ◽  
X Ray

The Structure and Phases of a Relaxed Langmuir Monolayer of Methyl Eicosanoate as Determined by Grazing Incidence Xray Diffraction and Brewster Angle Microscopy

1994 ◽  
Vol 375 ◽  
Author(s):  
W. J. Foster ◽  
M. C. Shih ◽  
P. S. Pershan
Keyword(s):  
Molecular Structure ◽  
Phase Diagram ◽  
Grazing Incidence ◽  
Brewster Angle ◽  
Water Interface ◽  
Brewster Angle Microscopy ◽  
X Ray Diffraction ◽  
Monolayer Films ◽  
X Ray ◽  
Air Water Interface

AbstractThe molecular structure and phase diagram of relaxed monolayer films of methyl eicosanoate at the air/water interface were studied using x-ray diffraction and Brewster Angle Microscopy. Six phases have been identified in relaxed films in a temperature range of 5 to 28 degrees Celsius.

scholarly journals Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Matthew B Stone ◽  
Sarah A Shelby ◽  
Marcos F Núñez ◽  
Kathleen Wisser ◽  
Sarah L Veatch
Keyword(s):  
Plasma Membranes ◽  
B Lymphocyte ◽  
Membrane Lipids ◽  
Super Resolution ◽  
Cell Receptor ◽  
Biochemical Networks ◽  
Lipid Phase ◽  
Intact Cells ◽  
Signaling Function ◽  
Liquid Ordered

Diverse cellular signaling events, including B cell receptor (BCR) activation, are hypothesized to be facilitated by domains enriched in specific plasma membrane lipids and proteins that resemble liquid-ordered phase-separated domains in model membranes. This concept remains controversial and lacks direct experimental support in intact cells. Here, we visualize ordered and disordered domains in mouse B lymphoma cell membranes using super-resolution fluorescence localization microscopy, demonstrate that clustered BCR resides within ordered phase-like domains capable of sorting key regulators of BCR activation, and present a minimal, predictive model where clustering receptors leads to their collective activation by stabilizing an extended ordered domain. These results provide evidence for the role of membrane domains in BCR signaling and a plausible mechanism of BCR activation via receptor clustering that could be generalized to other signaling pathways. Overall, these studies demonstrate that lipid mediated forces can bias biochemical networks in ways that broadly impact signal transduction.

scholarly journals Biomedical Graph Visualizer for Identifying Drug Candidates

2020 ◽  
Author(s):  
Ashton Teng ◽  
Blanca Villanueva ◽  
Derek Jow ◽  
Shih-Cheng (Mars) Huang ◽  
Samantha N. Piekos ◽  
...  
Keyword(s):  
Drug Development ◽  
De Novo ◽  
Drug Candidate ◽  
Knowledge Graph ◽  
Major Barrier ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Computational Discovery ◽  
Complex Relationships ◽  
User Friendly

1.AbstractMillions of Americans suffer from illnesses with non-existent or ineffective drug treatment. Identifying plausible drug candidates is a major barrier to drug development due to the large amount of time and resources required; approval can take years when people are suffering now. While computational tools can expedite drug candidate discovery, these tools typically require programming expertise that many biologists lack. Though biomedical databases continue to grow, they have proven difficult to integrate and maintain, and non-programming interfaces for these data sources are scarce and limited in capability. This creates an opportunity for us to present a suite of user-friendly software tools to aid computational discovery of novel treatments through de novo discovery or repurposing. Our tools eliminate the need for researchers to acquire computational expertise by integrating multiple databases and offering an intuitive graphical interface for analyzing these publicly available data. We built a computational knowledge graph focused on biomedical concepts related to drug discovery, designed visualization tools that allow users to explore complex relationships among entities in the graph, and served these tools through a free and user-friendly web interface. We show that users can conduct complex analyses with relative ease and that our knowledge graph and algorithms recover approved repurposed drugs. Our evaluation indicates that our method provides an intuitive, easy, and effective toolkit for discovering drug candidates. We show that our toolkit makes computational analysis for drug development more accessible and efficient and ultimately plays a role in bringing effective treatments to all patients.Our application is hosted at: https://biomedical-graph-visualizer.wl.r.appspot.com/

Sign in / Sign up

Export Citation Format

Share Document