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Core A - Discovery Core

核心 A - 发现核心

基本信息

批准号：
10683121
负责人：
Jeffrey L Benovic
金额：
$ 29.46万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683121
关键词：
Adrenergic Receptor Affect Affinity Agonist Airway Disease Arrestins Asthma Back Binding Biochemical Biological Assay Bronchodilation Cells Chemicals Complement Complex Computer Models Computing Methodologies Cyclic AMP Data Detection Development Disease Docking Ensure Enzymes Evaluation Fluorescence-Activated Cell Sorting G-Protein-Coupled Receptors GPR68 gene Genomics Human Infrastructure Knowledge Lead Libraries Ligands Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinic Acetylcholine Receptor M3 Muscle Contraction Natural Products Pathway interactions Peptide Library Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Actions Phenotype Play Population Private Sector Property Proteins Public Sector Quinazolines Relaxation Resources Role Second Messenger Systems Signal Pathway Signal Transduction Source Specificity Structure Structure-Activity Relationship Study models Surface Plasmon Resonance Testing Vestibule airway inflammation constriction design effective therapy extracellular high throughput screening improved inhibitor innovation lead candidate lead optimization novel respiratory smooth muscle screening small molecule small molecule inhibitor success synergism translational applications virtual screening

项目摘要

Project Summary The screening core will build on our success utilizing conventional and virtual screening approaches to identify small molecules that regulate bronchomotor tone. The integration of conventional and virtual screening workflows enabled us to move rapidly from primary screening hits to detailed structure-activity relationships (SAR), and from computational predictions to quantitative experimental data. The relationships that the core has established with other regional screening resources (Lankenau Chemical Genomics Center (LCGC); Natural Products Discovery Institute (NPDI); Monell Chemical Senses Center (MCSC)) ensures access to high-quality molecular diversity for proposed screening projects, and our validated expertise in second messenger and protein interaction assays will expedite discovery of probes and targets that bias signaling pathways in airway smooth muscle using arrayed and expressed sources of molecular diversity. The Jefferson Discovery Core provides the conventional screening capabilities for Core A, using in- house sources of molecular diversity as well as libraries obtained from regional and national resources (NCI- DTP) to identify small molecules engendering phenotypes that correlate with airway relaxation in cell-based, high-throughput screening (HTS) assays. Second messenger (cAMP, Ca2+) and protein interaction assays (enzyme-fragment complementation) have been optimized for detection both in multiwell plates and by fluorescence-activated cell sorting, which enables use of both arrayed and expressed sources of molecular diversity for identification of probes and targets regulating signaling pathways affecting bronchomotor tone. HTS for inhibitors of G12 signaling (project 1), internalization of TAS2R14 (project 2), HTS, SAR and medicinal chemistry to discover and optimize Gs-biased agonists and allosteric modulators of 2AR (project 3) and evaluation of Gs-biased allosteric modulators of OGR1 predicted by virtual screening (project 4) are the top priorities. Computational modeling and docking approaches are used by Core A both to direct and inform conventional screening approaches. CHARMM-based molecular docking approaches will be used to predict the binding modes of small-molecules identified from high-throughput screening, develop SAR models and predict derivatives with improved activity and physiochemical properties. These studies are synergistic with parallel experimental HTS efforts, particularly in following-up on the most promising hits identified from HTS. Parallel modeling studies of small-molecule allosteric modulators of 2AR and OGR1 will be aimed at identifying common structural features leading to Gs-biased signaling. Structure-based knowledge will be used to inform parallel virtual screening strategies to identify novel allosteric modulators of 2AR and OGR1. Finally, a virtual screening approach will be used to identify small-molecule inhibitors of G12 and Gq that would mimic the pharmacological action of the Gq specific inhibitor YM-254890.

项目总结