Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation
| Autor: | Xun Li, De-Xin Kong, Mengyao Guo, Yi Liu, Dong Wang, Nianhang Chen, Ren-Yuan Hong |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Monoamine Oxidase Inhibitors
Structural similarity Monoamine oxidase Pharmaceutical Science Subtype selectivity 01 natural sciences Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences Structure-Activity Relationship in silico pharmacokinetic predictions lcsh:Organic chemistry Coumarins Cell Line Tumor Drug Discovery Humans Physical and Theoretical Chemistry Monoamine Oxidase 030304 developmental biology chemistry.chemical_classification 0303 health sciences 010405 organic chemistry Chemistry BRS-3D Organic Chemistry MAO inhibitors Brain subtype selectivity Combinatorial chemistry Sequence identity molecular dynamic simulations 0104 chemical sciences Molecular Docking Simulation Enzyme Chemistry (miscellaneous) Docking (molecular) Molecular Medicine Caco-2 Cells Selectivity monoamine oxidase (MAO) inhibitors Protein Binding |
| Zdroj: | Molecules Volume 24 Issue 21 Molecules, Vol 24, Iss 21, p 4003 (2019) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules24214003 |
| Popis: | There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. &ldquo Three-Dimensional Biologically Relevant Spectrum (BRS-3D)&rdquo method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) < &minus 2.82) and 19 nM (SI < 2.42), respectively. FR4 and FR5 showed the most potent hMAO-B inhibitory activity, with IC50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles. |
| Databáze: | OpenAIRE |
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