A5070197339- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Pharmacogenetics and Drug Metabolism
- Chemical Synthesis and Analysis
- Neuroscience and Neuropharmacology Research
- Click Chemistry and Applications
- Pharmaceutical Economics and Policy
- Amyotrophic Lateral Sclerosis Research
- Antibiotic Resistance in Bacteria
- Microbial Natural Products and Biosynthesis
- Chemical Reaction Mechanisms
- Amino Acid Enzymes and Metabolism
- Neuropeptides and Animal Physiology
- Synthesis and Characterization of Pyrroles
- Cancer-related gene regulation
- Pharmaceutical studies and practices
- Bioactive Compounds and Antitumor Agents
- Metabolism and Genetic Disorders
- Cancer therapeutics and mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- Neurogenetic and Muscular Disorders Research
- Health Systems, Economic Evaluations, Quality of Life
- Historical Medical Research and Treatments
AstraZeneca (United States)
2014-2025
Jnana Therapeutics (United States)
2020-2025
Brookhaven National Laboratory
2023
AstraZeneca (United Kingdom)
2006-2016
Wilmington University
2003-2010
Hôpital Broussais
2010
Shell (Netherlands)
2006
Hamline University
1996-1998
University of Minnesota
1988-1998
University of Hertfordshire
1997
An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and natural product total synthesis has been conducted. The revealed that the most frequently synthetic reactions, none were discovered within past 20 years only two 1980s 1990s (Suzuki-Miyaura Buchwald-Hartwig). This suggests an inherent high bar impact for new drug discovery. amide bond formation, Suzuki-Miyaura coupling, SNAr likely due to commercial availability reagents,...
To better understand the difficulties surrounding identification of novel antibacterial compounds from corporate screening collections, physical properties ∼3200 project with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found high throughput (HTS) screens conducted on both biochemical phenotypic bacterial targets. The output 23 HTS illustrated that when compounds, significantly more hydrophobic than (typically 2-4 log units...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation p38 mitogen-activated protein kinase (MAPK) implicated in ALS. However, it unclear how MAPK affects proteinopathy. Here, we show that p38α inhibition reduces pathological phosphorylation, aggregation, cytoplasmic mislocalization, and...
Abstract Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce burden human neurons and, from small-molecule screen, identify mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds more potent than rapamycin, robustly downregulate...
A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization sulfonyl piperazine pyrazole compounds, each with mechanisms action. E. mutants resistant these compounds display no cross-resistance antibiotics other classes. Resistance maps LpxH, which...
Demonstration of target binding is a key requirement for understanding the mode action new therapeutics. The cellular thermal shift assay (CETSA) has been introduced as powerful label-free method to assess engagement in physiological environments. Here, we present application live-cell CETSA different classes integral multipass transmembrane proteins using three case studies, first showing large and robust stabilization outer mitochondrial five-pass protein TSPO, second being modest SERCA2,...
We report here an unexpectedly strong preference toward para substitution in phenyl rings within drug discovery programs. A population analysis of aromatic various databases demonstrated that is favored over meta and ortho regioisomers, with p-chlorophenyl (p-ClPh) being one the most predominant examples. speculate frequency p-ClPh traced back to historical models medicinal chemistry where para-substituted regioisomers were perhaps more easily accessed, further reinforced by Topliss 1972 if...
The discovery of ligands via affinity-mediated selection DNA-encoded chemical libraries is driven by the quality and concentration protein target. G-protein-coupled receptors (GPCRs) other membrane-bound targets can be difficult to isolate in their functional state at high concentrations, therefore have been challenging for selection. Here, we report a successful campaign against protease-activated receptor 2 (PAR2). Using thermo-stabilized mutant PAR2, conducted affinity using our...
ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTA Convenient Synthesis of Dimethyl (Diazomethyl)phosphonate (Seyferth/Gilbert Reagent)Dean G. Brown, Emil J. Velthuisen, Jessica R. Commerford, Ronald Brisbois, and View Author Information University Minnesota, Minneapolis, Minnesota 55455 Hamline University, St. Paul, 55104 Cite this: Org. Chem. 1996, 61, 7, 2540–2541Publication Date (Web):April 5, 1996Publication History Received1 November 1995Published online5 April 1996Published inissue 1 January...
Abstract Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of potent new agonist, suggested by molecular modelling bind putative orthosteric site, two novel PAR2 antagonists with distinctly different mechanisms inhibition. We identify coupling between binding sites. One antagonist competitive inhibitor...