Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis
| Autor: | Alaattin Sen, Ali Dişli, Atilla Akdemir, Doğukan Doyduk, Gurbet Çelik Turgut, Yılmaz Yıldırır, Serkan Yavuz |
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| Přispěvatelé: | YAVUZ, SELDA |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
synthesis Clinical Biochemistry Response element Pharmaceutical Science drug protein binding Pharmacology multiple sclerosis Biochemistry Neuroblastoma 0302 clinical medicine dose response Drug Discovery binding affinity Tumor Cells Cultured Receptor Receptor modulator cyclic AMP responsive element binding protein Molecular Structure Chemistry computer aided design myelination gene expression regulation Fingolimod unclassified drug Molecular Docking Simulation 2 amino 2 [2 (1 octyl 1h tetrazol 5 yl)ethyl]propane 1 3 diol hydrochloride neuromodulation Molecular Medicine cAMP-dependent pathway Computer-Aided Design 3 amino 3 (hydroxymethyl) 1 [4 (1 octyl 1h tetrazol 5 yl)phenyl]butan 1 4 diol hydrocloride antiinflammatory agent signal transduction medicine.drug crystal structure Cell Survival/drug effects Dose-Response Relationship Drug Fingolimod Hydrochloride/*chemical synthesis/*pharmacology/therapeutic use Humans Multiple Sclerosis/*drug therapy Structure-Activity Relationship drug design Cell Survival S1P1 agonists Article 03 medical and health sciences Cell surface receptor medicine gene expression profiling controlled study human immunoassay fingolimod Molecular Biology Transcription factor hydrophobicity structure activity relation Fingolimod Hydrochloride Multiple sclerosis human cell Organic Chemistry molecular docking tumor cell culture medicine.disease Multiple sclerosis (MS) TURGUT G. DOYDUK D. YıLDıRıR Y. YAVUZ S. Akdemir A. DIŞLI A. ŞEN A. -Computer design synthesis and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis.- Bioorganic & medicinal chemistry cilt.25 ss.483-495 2017 drug efficacy 030104 developmental biology drug effects chemical structure drug synthesis Molecular modeling studies molecular model Glioblastoma 030217 neurology & neurosurgery |
| Popis: | Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118 MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS-and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the CAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis. (C) 2016 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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