Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist
| Autor: | Naohiro Taya, Chien-Hung Chen, Tsuneo Oda, Bi-Ching Sang, Tomoya Yukawa, Takayuki Sato, Yoshi Nara, Noriko Uchiyama, Zenyu Shiokawa, Terufumi Takagi, Satoshi Yamamoto, Ayumu Sato, Ryokichi Koyama, Nobuyuki Negoro, Gyorgy Snell, Junya Shirai, Ryosuke Katsuyama, Takashi Imada, Yoshihiro Banno, Isaac Hoffman, Tetsuji Kawamoto, Mitsunori Kono, Robert J. Skene |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Drug Inverse Agonism medicine.drug_class Retinoic acid Molecular Dynamics Simulation 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship RAR-related orphan receptor gamma Drug Discovery medicine Inverse agonist Structure–activity relationship Animals 030304 developmental biology Orphan receptor 0303 health sciences Chemistry Nuclear Receptor Subfamily 1 Group F Member 3 0104 chemical sciences Cell biology High-Throughput Screening Assays 010404 medicinal & biomolecular chemistry Design synthesis Drug Design Molecular Medicine Th17 Cells |
| Zdroj: | Journal of medicinal chemistry. 62(3) |
| ISSN: | 1520-4804 |
| Popis: | Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists. |
| Databáze: | OpenAIRE |
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