Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d
| Autor: | Gorham, RD, Nuñez, V, Lin, JH, Rooijakkers, SHM, Vullev, VI, Morikis, D |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Protein Conformation
1.1 Normal biological development and functioning Medicinal & Biomolecular Chemistry Organic Chemistry chemical and pharmacologic phenomena Pharmacology and Pharmaceutical Sciences Ligands Small Molecule Libraries Molecular Docking Simulation Structure-Activity Relationship Medicinal and Biomolecular Chemistry Underpinning research Complement C3d 5.1 Pharmaceuticals Development of treatments and therapeutic interventions Complement Activation Fluorescent Dyes |
| Zdroj: | Journal of medicinal chemistry, vol 58, iss 24 Gorham, RD; Nuñez, V; Lin, JH; Rooijakkers, SHM; Vullev, VI; & Morikis, D. (2015). Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d. Journal of Medicinal Chemistry, 58(24), 9535-9545. doi: 10.1021/acs.jmedchem.5b01062. UC Riverside: Retrieved from: http://www.escholarship.org/uc/item/2888860h |
| DOI: | 10.1021/acs.jmedchem.5b01062. |
| Popis: | © 2015 American Chemical Society. Complement activation plays a major role in many acute and chronic inflammatory conditions. C3d, a terminal product of complement activation, remains covalently attached to cells and is an excellent biomarker of complement-mediated inflammation. We employed a virtual high-throughput screening protocol to identify molecules with predicted binding to complement C3d and with intrinsic fluorescence properties to enable detection. Pharmacophore models were developed based on known C3d-ligand interactions and information from computational analysis of structural and molecular dynamics data. Iterative pharmacophore-based virtual screening was performed to identify druglike molecules with physicochemical similarity to the natural C3d ligand CR2. Hits from the pharmacophore screens were docked to C3d and ranked based on predicted binding free energies. Top-ranked molecules were selected for experimental validation of binding affinity to C3d, using microscale thermophoresis, and for their suitability to become molecular imaging agents, using fluorescence spectroscopy. This work serves as a foundation for identifying additional fluorescent molecules with high-affinity for C3d that will subsequently be explored as noninvasive in vivo diagnostics of complement-mediated inflammation, for spatiotemporal monitoring of disease progression, and for targeting therapeutics to sites of inflammation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|