Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists
| Autor: | Antonella Ciancetta, Leah Birdwell, Anna Junker, Ramachandran Balasubramanian, Kevin Trujillo, Chiara Martiriggiano, Kenneth A. Jacobson, T. Kendall Harden, Evgeny Kiselev, Giorgi Mtchedlidze, Elisa Uliassi, Kyle A. Brown |
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| Přispěvatelé: | Junker, Anna, Balasubramanian, Ramachandran, Ciancetta, Antonella, Uliassi, Elisa, Kiselev, Evgeny, Martiriggiano, Chiara, Trujillo, Kevin, Mtchedlidze, Giorgi, Birdwell, Leah, Brown, Kyle A., Harden, T. Kendall, Jacobson, Kenneth A |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Alkyne Pharmaceutical Science CHO Cells Molecular Dynamics Simulation 01 natural sciences Molecular Docking Simulation Article NO Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cricetulus Drug Discovery Purinergic P2 Receptor Antagonists Animals Humans Structure–activity relationship Homology modeling chemistry.chemical_classification Receptors Purinergic P2 010405 organic chemistry Aryl Biphenyl Compounds Antagonist Triazoles Affinities Combinatorial chemistry 0104 chemical sciences 3. Good health 030104 developmental biology chemistry Docking (molecular) Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry |
| Popis: | UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models. |
| Databáze: | OpenAIRE |
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