Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors
In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affin...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Sethi, Aaftaab [verfasserIn] Sasikala, K. [verfasserIn] Jakkula, Pranay [verfasserIn] Gadde, Divya [verfasserIn] Sanam, Swetha [verfasserIn] Qureshi, Insaf A. [verfasserIn] Talla, Venu [verfasserIn] Alvala, Mallika [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Chemical papers - Wien : Springer Vienna, 1947, 75(2021), 6 vom: 02. Feb., Seite 2791-2805 |
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| Übergeordnetes Werk: |
volume:75 ; year:2021 ; number:6 ; day:02 ; month:02 ; pages:2791-2805 |
| Links: |
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| DOI / URN: |
10.1007/s11696-021-01534-w |
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| Katalog-ID: |
SPR043861776 |
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| 520 | |a In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract | ||
| 650 | 4 | |a Galectins |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Galectin-1 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Gal-1 inhibitors |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Non-carbohydrate inhibitors |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Indole-coumarin hybrids |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Chalcones |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Sasikala, K. |e verfasserin |4 aut | |
| 700 | 1 | |a Jakkula, Pranay |e verfasserin |4 aut | |
| 700 | 1 | |a Gadde, Divya |e verfasserin |4 aut | |
| 700 | 1 | |a Sanam, Swetha |e verfasserin |4 aut | |
| 700 | 1 | |a Qureshi, Insaf A. |e verfasserin |4 aut | |
| 700 | 1 | |a Talla, Venu |e verfasserin |4 aut | |
| 700 | 1 | |a Alvala, Mallika |e verfasserin |4 aut | |
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| 912 | |a GBV_ILN_2088 | ||
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10.1007/s11696-021-01534-w doi (DE-627)SPR043861776 (DE-599)SPRs11696-021-01534-w-e (SPR)s11696-021-01534-w-e DE-627 ger DE-627 rakwb eng 540 ASE 35.00 bkl Sethi, Aaftaab verfasserin aut Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 Sasikala, K. verfasserin aut Jakkula, Pranay verfasserin aut Gadde, Divya verfasserin aut Sanam, Swetha verfasserin aut Qureshi, Insaf A. verfasserin aut Talla, Venu verfasserin aut Alvala, Mallika verfasserin aut Enthalten in Chemical papers Wien : Springer Vienna, 1947 75(2021), 6 vom: 02. Feb., Seite 2791-2805 (DE-627)518347737 (DE-600)2252770-9 1336-9075 nnns volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 https://dx.doi.org/10.1007/s11696-021-01534-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 35.00 ASE AR 75 2021 6 02 02 2791-2805 |
| spelling |
10.1007/s11696-021-01534-w doi (DE-627)SPR043861776 (DE-599)SPRs11696-021-01534-w-e (SPR)s11696-021-01534-w-e DE-627 ger DE-627 rakwb eng 540 ASE 35.00 bkl Sethi, Aaftaab verfasserin aut Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 Sasikala, K. verfasserin aut Jakkula, Pranay verfasserin aut Gadde, Divya verfasserin aut Sanam, Swetha verfasserin aut Qureshi, Insaf A. verfasserin aut Talla, Venu verfasserin aut Alvala, Mallika verfasserin aut Enthalten in Chemical papers Wien : Springer Vienna, 1947 75(2021), 6 vom: 02. Feb., Seite 2791-2805 (DE-627)518347737 (DE-600)2252770-9 1336-9075 nnns volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 https://dx.doi.org/10.1007/s11696-021-01534-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 35.00 ASE AR 75 2021 6 02 02 2791-2805 |
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10.1007/s11696-021-01534-w doi (DE-627)SPR043861776 (DE-599)SPRs11696-021-01534-w-e (SPR)s11696-021-01534-w-e DE-627 ger DE-627 rakwb eng 540 ASE 35.00 bkl Sethi, Aaftaab verfasserin aut Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 Sasikala, K. verfasserin aut Jakkula, Pranay verfasserin aut Gadde, Divya verfasserin aut Sanam, Swetha verfasserin aut Qureshi, Insaf A. verfasserin aut Talla, Venu verfasserin aut Alvala, Mallika verfasserin aut Enthalten in Chemical papers Wien : Springer Vienna, 1947 75(2021), 6 vom: 02. Feb., Seite 2791-2805 (DE-627)518347737 (DE-600)2252770-9 1336-9075 nnns volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 https://dx.doi.org/10.1007/s11696-021-01534-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 35.00 ASE AR 75 2021 6 02 02 2791-2805 |
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10.1007/s11696-021-01534-w doi (DE-627)SPR043861776 (DE-599)SPRs11696-021-01534-w-e (SPR)s11696-021-01534-w-e DE-627 ger DE-627 rakwb eng 540 ASE 35.00 bkl Sethi, Aaftaab verfasserin aut Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 Sasikala, K. verfasserin aut Jakkula, Pranay verfasserin aut Gadde, Divya verfasserin aut Sanam, Swetha verfasserin aut Qureshi, Insaf A. verfasserin aut Talla, Venu verfasserin aut Alvala, Mallika verfasserin aut Enthalten in Chemical papers Wien : Springer Vienna, 1947 75(2021), 6 vom: 02. Feb., Seite 2791-2805 (DE-627)518347737 (DE-600)2252770-9 1336-9075 nnns volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 https://dx.doi.org/10.1007/s11696-021-01534-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 35.00 ASE AR 75 2021 6 02 02 2791-2805 |
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10.1007/s11696-021-01534-w doi (DE-627)SPR043861776 (DE-599)SPRs11696-021-01534-w-e (SPR)s11696-021-01534-w-e DE-627 ger DE-627 rakwb eng 540 ASE 35.00 bkl Sethi, Aaftaab verfasserin aut Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 Sasikala, K. verfasserin aut Jakkula, Pranay verfasserin aut Gadde, Divya verfasserin aut Sanam, Swetha verfasserin aut Qureshi, Insaf A. verfasserin aut Talla, Venu verfasserin aut Alvala, Mallika verfasserin aut Enthalten in Chemical papers Wien : Springer Vienna, 1947 75(2021), 6 vom: 02. Feb., Seite 2791-2805 (DE-627)518347737 (DE-600)2252770-9 1336-9075 nnns volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 https://dx.doi.org/10.1007/s11696-021-01534-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 35.00 ASE AR 75 2021 6 02 02 2791-2805 |
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Enthalten in Chemical papers 75(2021), 6 vom: 02. Feb., Seite 2791-2805 volume:75 year:2021 number:6 day:02 month:02 pages:2791-2805 |
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Galectins Galectin-1 Gal-1 inhibitors Non-carbohydrate inhibitors Indole-coumarin hybrids Chalcones |
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Sethi, Aaftaab @@aut@@ Sasikala, K. @@aut@@ Jakkula, Pranay @@aut@@ Gadde, Divya @@aut@@ Sanam, Swetha @@aut@@ Qureshi, Insaf A. @@aut@@ Talla, Venu @@aut@@ Alvala, Mallika @@aut@@ |
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Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. 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Sethi, Aaftaab |
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Sethi, Aaftaab ddc 540 bkl 35.00 misc Galectins misc Galectin-1 misc Gal-1 inhibitors misc Non-carbohydrate inhibitors misc Indole-coumarin hybrids misc Chalcones Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors |
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540 ASE 35.00 bkl Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors Galectins (dpeaa)DE-He213 Galectin-1 (dpeaa)DE-He213 Gal-1 inhibitors (dpeaa)DE-He213 Non-carbohydrate inhibitors (dpeaa)DE-He213 Indole-coumarin hybrids (dpeaa)DE-He213 Chalcones (dpeaa)DE-He213 |
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ddc 540 bkl 35.00 misc Galectins misc Galectin-1 misc Gal-1 inhibitors misc Non-carbohydrate inhibitors misc Indole-coumarin hybrids misc Chalcones |
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ddc 540 bkl 35.00 misc Galectins misc Galectin-1 misc Gal-1 inhibitors misc Non-carbohydrate inhibitors misc Indole-coumarin hybrids misc Chalcones |
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ddc 540 bkl 35.00 misc Galectins misc Galectin-1 misc Gal-1 inhibitors misc Non-carbohydrate inhibitors misc Indole-coumarin hybrids misc Chalcones |
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Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors |
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Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors |
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Sethi, Aaftaab |
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Sethi, Aaftaab Sasikala, K. Jakkula, Pranay Gadde, Divya Sanam, Swetha Qureshi, Insaf A. Talla, Venu Alvala, Mallika |
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10.1007/s11696-021-01534-w |
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design, synthesis and computational studies involving indole-coumarin hybrids as galectin-1 inhibitors |
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Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors |
| abstract |
In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract |
| abstractGer |
In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract |
| abstract_unstemmed |
In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant ($ K_{a} $) value of 5.4 × $ 10^{5} $ $ M^{−1} $ while 7e was found to have a slightly higher affinity than 6i with $ K_{a} $ of 6.6 × $ 10^{5} $ $ M^{−1} $. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract |
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Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors |
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| score |
7.4011116 |