Development of Posaconazole-based Analogues as Hedgehog Signaling Pathway Inhibitors
| Autor: | Robert J. Wechsler-Reya, Radha Charan Dash, M. Kyle Hadden, Shana R. Morel, Kelly A. Teske, Lianne Q. Chau |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Posaconazole
Antifungal Agents Itraconazole Triazole Pharmacology Molecular Dynamics Simulation 01 natural sciences Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Humans Hedgehog Proteins Binding site Hedgehog 030304 developmental biology 0303 health sciences 010405 organic chemistry Organic Chemistry General Medicine Triazoles Ligand (biochemistry) Smoothened Receptor Hedgehog signaling pathway 0104 chemical sciences chemistry Carcinoma Basal Cell Smoothened medicine.drug Protein Binding Signal Transduction |
| Popis: | Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|