A5044595013- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Advanced NMR Techniques and Applications
- NMR spectroscopy and applications
- Cardiac electrophysiology and arrhythmias
- Effects and risks of endocrine disrupting chemicals
- DNA and Nucleic Acid Chemistry
- Advanced MRI Techniques and Applications
- Receptor Mechanisms and Signaling
- Machine Learning in Materials Science
- Estrogen and related hormone effects
- Enzyme Structure and Function
- Pharmacogenetics and Drug Metabolism
- RNA and protein synthesis mechanisms
- Analytical chemistry methods development
- Hemophilia Treatment and Research
- Carcinogens and Genotoxicity Assessment
- Blood Coagulation and Thrombosis Mechanisms
- Biotin and Related Studies
- Research Data Management Practices
- Chemical and Physical Properties in Aqueous Solutions
- Alkaline Phosphatase Research Studies
- Hormonal and reproductive studies
- Animal testing and alternatives
- Pregnancy and preeclampsia studies
Pfizer (United States)
2022-2025
PRX Research
2024
Environmental Protection Agency
2016-2018
Research Triangle Park Foundation
2016-2018
Oak Ridge Associated Universities
2016-2018
University of Illinois Urbana-Champaign
2013-2016
Urbana University
2014
Yale University
2007-2011
University of Michigan
2006-2008
Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions dollars and take decades complete using current validated methods. High-throughput in vitro screening (HTS) computational toxicology approaches can more rapidly inexpensively androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 assays into a network model distinguish true AR pathway activity from technology-specific assay interference. The probed perturbations the...
Using a domain elongation strategy, we decoupled internal motions in RNA from overall rotational diffusion. This allowed us to site-specifically resolve manifold of motional modes two regulatory RNAs HIV-1 with the use nuclear magnetic resonance spin relaxation methods. Base and sugar librations vary on picosecond time scale occur within helical domains that move collectively at diffusion-limited nanosecond scales. Pivot points are short, functionally important, highly mobile loops. These...
The ability to use conformational flexibility is a hallmark of enzyme function. Here we show that protein motions and catalytic activity in RNase are coupled display identical solvent isotope effects. Solution NMR relaxation experiments identify cluster residues, some distant from the active site, integral this motion. These studies implicate single residue, histidine-48, as key modulator coupling motion with Mutation H48 alanine results loss isotope-sensitive region enzyme. In addition,...
High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening MIEs specific TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast assay portfolio. To fill 1 critical gap, Amplex UltraRed-thyroperoxidase (AUR-TPO) was developed identify inhibit TPO, as decreased TPO activity reduces TH synthesis. The...
Amide proton NMR signals from the N-terminal domain of monomeric alpha-synuclein (alphaS) are lost when sample temperature is raised 10 degrees C to 35 at pH 7.4. Although temperature-induced effects have been attributed conformational exchange caused by an increase in alpha-helix structure, we show that loss due fast amide exchange. At low ionic strength, hydrogen rates faster for segment alphaS than acidic C-terminal domain. When salt concentration 300 mM, throughout protein and become...
The role of the flexible loop 1 in protein conformational motion and dissociation enzymatic product from ribonuclease A (RNase A) was investigated by creation a chimeric enzyme which 6-residue RNase homologue, eosinophil cationic (ECP), replaced 12-residue A. chimera AECP) experiences only local perturbations NMR backbone chemical shifts compared to WT Many residues that were previously identified as involved an important change now experience no NMR-detected millisecond motions chimera....
High throughput screening (HTS) projects like the U.S. Environmental Protection Agency's ToxCast program are required to address large and rapidly increasing number of chemicals for which we have little no toxicity measurements. Concentration-response parameters such as potency efficacy extracted from HTS data using nonlinear regression, models analyses built these used predict in vivo vitro thousands chemicals. How predictions impacted by uncertainties that stem parameter estimation...
<title>Abstract</title> The link between in vitro hERG ion channel inhibition and subsequent vivo QT interval prolongation, a critical risk factor for the development of arrythmias such as Torsade de Pointes, is so well established that activity alone often sufficient to end an otherwise promising drug candidate. It therefore tremendous interest develop advanced methods identifying hERG-active compounds early stages development, proposing redesigned with reduced liability preserved primary...
The link between in vitro hERG ion channel inhibition and subsequent vivo QT interval prolongation, a critical risk factor for the development of arrythmias such as Torsade de Pointes, is so well established that activity alone often sufficient to end an otherwise promising drug candidate. It therefore tremendous interest develop advanced methods identifying hERG-active compounds early stages development, proposing redesigned with reduced liability preserved primary pharmacology. In this...
Thyroperoxidase (TPO) is the enzyme that synthesizes thyroid hormones (THs). TPO inhibition by chemicals can result in decreased TH levels and developmental neurotoxicity, therefore identification of high relevance safety evaluation chemicals. In present study, we developed two global quantitative structure–activity relationship (QSAR) models for vitro. Rigorous cross- blinded external validations demonstrated first model, QSAR1, built from a training set 877 chemicals, was robust highly...
Understanding the potential carcinogenic potency of nitrosamines is necessary to setting acceptable intake limits. Nitrosamines and components that can form them are commonly present in food, water, cosmetics, tobacco. The recent observation pharmaceuticals highlighted need for effective methods determine Herein, we describe two computational models utilize properties based upon quantum mechanical calculations conjunction with mechanistic insights established data a variety common...
Abstract For all the promise of and need for clinical drug-induced liver injury (DILI) risk screening systems, demonstrating predictive value these systems versus readily available physicochemical properties inherent dosing information has not been thoroughly evaluated. Therefore, we utilized a systematic approach to evaluate in vitro safety assays including bile salt export pump transporter inhibition cytotoxicity HepG2 transformed human epithelial along with properties. We also evaluated...
Drug-induced cardiotoxicity is a major health concern which can lead to serious adverse effects including life-threatening cardiac arrhythmias via the blockade of voltage-gated hERG potassium ion channel. It therefore tremendous interest develop advanced methods identify hERG-active compounds in early stages drug development, as well optimize commercially available drugs for reduced activity. In this work, we present CardioGenAI, machine learning-based framework re-engineering both...
ICH Q3A/B guidelines provide qualification thresholds for impurities or degradation products in new drug substances and products. However, the note that certain impurities/degradation may warrant further safety evaluation being unusually potent toxic. The purpose of this study was to confirm especially toxic non-mutagenic compounds are rare identify classes could lower thresholds. A total 2815 were evaluated, which 2213 assessed as non-mutagenic. For analysis, considered when point departure...
In normal hemostasis, the blood clotting cascade is initiated when factor VIIa (fVIIa, other factors are named similarly) binds to integral membrane protein, human tissue (TF). The TF/fVIIa complex in turn activates fX and fIX, eventually concluding with clot formation. Several X-ray crystal structures of soluble extracellular domain TF (sTF) exist; however, these missing electron density functionally relevant regions protein. this context, NMR can provide complementary structural...