A5036261394- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Lysosomal Storage Disorders Research
- Neurotransmitter Receptor Influence on Behavior
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Pregnancy-related medical research
- bioluminescence and chemiluminescence research
- Analytical Chemistry and Chromatography
- Radiopharmaceutical Chemistry and Applications
- Carbohydrate Chemistry and Synthesis
- Cancer, Hypoxia, and Metabolism
- Inorganic and Organometallic Chemistry
- Hepatitis C virus research
- Medical Imaging Techniques and Applications
- Animal testing and alternatives
- Calcium signaling and nucleotide metabolism
- Pharmacogenetics and Drug Metabolism
- Trypanosoma species research and implications
- Analytical Methods in Pharmaceuticals
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Protein Structure and Dynamics
- RNA modifications and cancer
National Institutes of Health
2015-2025
National Center for Advancing Translational Sciences
2015-2025
AstraZeneca (United States)
2022-2024
National Patient Safety Foundation
2022-2023
University of Washington
2022
North Carolina State University
2022
Clinical Innovations (United States)
2020
University of Kansas
2018-2019
Leidos (United States)
2019
Leidos Biomedical Research Inc. (United States)
2019
Oil and water do not mix. The disaffinity of oil for water, with its unusual temperature dependence, is called the hydrophobic effect. It important to understand factors underlying effect because they appear play key roles in membrane micelle formation, protein folding, ligand-protein protein−protein binding, chromatographic retention, possibly nucleic acid interactions, partitioning drugs, metabolites, toxins throughout environment living systems. Here, we survey experimental theoretical...
We model ion solvation in water. use the MB of water, a simple two-dimensional statistical mechanical which waters are represented as Lennard-Jones disks having Gaussian hydrogen-bonding arms. introduce charge dipole into waters. perform (NPT) Monte Carlo simulations to explore how water molecules organized around ions and nonpolar solutes salt solutions. The gives good qualitative agreement with experiments, including Jones-Dole viscosity B coefficients, Samoilov Hirata hydration activation...
Small-molecule compounds approved for use as drugs may be "repurposed" new indications and studied to determine the mechanisms of their beneficial adverse effects. A comprehensive collection all small-molecule human would invaluable systematic repurposing across diseases, particularly rare neglected which cost time required development a chemical entity are often prohibitive. Previous efforts build such have been limited by complexities, redundancies, semantic inconsistencies drug naming...
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy homeostasis biosynthesis. Although little is known about lipid droplet formation regulation, it clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein 47 kDa) family coat surface mediate interactions with lipases remobilize stored lipids. We identified key Drosophila candidate genes regulation by RNA interference (RNAi) screening an image...
Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this is co-opted into contributing toward tumor growth instead preventing its progression. We seek to reestablish an antitumor by selectively targeting surface receptors and endogenous signaling processes macrophage subtypes driving cancer RP-182 synthetic 10-mer amphipathic analog host defense peptides that induces conformational switch mannose receptor CD206...
The 'druggable genome' encompasses several protein families, but only a subset of targets within them have attracted significant research attention and thus information about publicly available. Illuminating the Druggable Genome (IDG) program was initiated in 2014, has goal developing experimental techniques Knowledge Management Center (KMC) that would collect organize from four representing most common druggable with an emphasis on understudied proteins. Here, we describe two resources...
Chemical genomics aims to comprehensively define, and ultimately predict, the effects of small molecule compounds on biological systems. activity profiling approaches must consider chemical all pathways operative in mammalian cells. To enable a strategic maximally efficient pathway space, we have created NCATS BioPlanet, comprehensive integrated resource that incorporates universe 1,658 human sourced from publicly available, manually curated sources, which been subjected thorough redundancy...
Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate and/or by aggressive prostate (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 were screened from the LOPAC library (a collection 1,280 pharmacologically active compounds) NPC (NCGC 3,300 approved use). Twenty-two found be either potent activators or inhibitors intracellular GFP...
Machine Intelligence (MI) is rapidly becoming an important approach across biomedical discovery, clinical research, medical diagnostics/devices, and precision medicine. Such tools can uncover new possibilities for researchers, physicians, patients, allowing them to make more informed decisions achieve better outcomes. When deployed in healthcare settings, these approaches have the potential enhance efficiency effectiveness of health research care ecosystem, ultimately improve quality patient...
Significance Lysosomes are the cell’s degradation center. To adapt to different environmental conditions, cell has evolved a set of delicate mechanisms rapidly change lysosome function, which is referred as lysosomal adaptation. Notably, adaptation required for survival under low nutrient conditions. In this study, we identified TRPML1, Ca 2+ -permeant ion channel, an essential player The activity TRPML1 potently (up 10-fold) and increased upon starvation. Furthermore, pharmacological...
Abstract In 2014, the National Institutes of Health (NIH) initiated Illuminating Druggable Genome (IDG) program to identify and improve our understanding poorly characterized proteins that can potentially be modulated using small molecules or biologics. Two resources produced from these efforts are: The Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/) Pharos (https://pharos.nih.gov/), a web interface browse TCRD. ultimate goal is highlight facilitate research...
Chromo/fluorophoric properties often accompany the heterocyclic scaffolds and impurities that comprise libraries used for high-throughput screening (HTS). These affect assay outputs obtained with optical detection, thus complicating analysis leading to false positives negatives. Here, we report fluorescence profile of more than 70 000 samples across spectral regions commonly utilized in HTS. The quantitative HTS paradigm was test each sample at seven or concentrations over a 4-log range...
The propensity of compounds to produce adverse health effects in humans is generally evaluated using animal-based test methods. Such methods can be relatively expensive, low-throughput, and associated with pain suffered by the treated animals. In addition, differences species biology may confound extrapolation human effects.The National Toxicology Program Institutes Health Chemical Genomics Center are collaborating identify a battery cell-based screens prioritize for further toxicologic...
We model the aqueous solvation of a nonpolar solute as function its radius. use simplified statistical mechanical water, Mercedes Benz (MB) model, in NPT Monte Carlo simulations. This has previously been shown to predict qualitatively volume anomalies pure water and free energy, enthalpy, entropy, heat capacity, change for inserting into water. find very different mechanism large solutes (much larger than water) smaller solutes. Small transfer involves hydrophobic capacity; disaffinity cold...
To aid in the interpretation of high-throughput screening (HTS) results derived from luciferase-based assays, we used quantitative HTS, an approach that defines concentration−response behavior each library sample, to profile ATP-dependent luciferase Photinus pyralis against more than 70 000 samples. We found approximately 3% was active, containing only compounds with inhibitory concentration−responses, which 681 (0.9%) exhibited IC50 < 10 µM. Representative were shown inhibit purified P. as...
The metabolism of cancer cells is altered to support rapid proliferation. Pharmacological activators a tumor cell specific pyruvate kinase isozyme (PKM2) may be an approach for altering the classic Warburg effect characteristic aberrant in yielding novel antiproliferation strategy. In this manuscript, we detail discovery series substituted N,N′-diarylsulfonamides as PKM2. synthesis numerous analogues and evaluation structure−activity relationships are presented well assessments mechanism...
Hepatitis C virus (HCV) infection affects an estimated 185 million people worldwide, with chronic often leading to liver cirrhosis and hepatocellular carcinoma. Although HCV is curable, there unmet need for the development of effective affordable treatment options. Through a cell-based high-throughput screen, we identified chlorcyclizine HCl (CCZ), over-the-counter drug allergy symptoms, as potent inhibitor infection. CCZ inhibited in human hepatoma cells primary hepatocytes. The mode action...
A major challenge in the field of Gaucher disease has been development new therapeutic strategies including molecular chaperones. All previously described chaperones glucocerebrosidase are enzyme inhibitors, which complicates their clinical because chaperone activity must be balanced against functional inhibition enzyme. Using a novel high throughput screening methodology, we identified chemical series that does not inhibit but can still facilitate its translocation to lysosome as measured...