Design, synthesis, evaluation, and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors
© 2020 Deutsche Pharmazeutische Gesellschaft..
A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 µM, followed by 8c (IC50 = 5.12 µM), compared with the standard drug, orlistat (IC50 = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a-f and 8a-f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of -163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π-π stacking and π-cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides (8a-d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:353 |
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| Enthalten in: |
Archiv der Pharmazie - 353(2020), 8 vom: 02. Aug., Seite e2000048 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sridhar, S N C [VerfasserIn] |
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| Links: |
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| Themen: |
ADME |
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| Anmerkungen: |
Date Completed 20.05.2021 Date Revised 20.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/ardp.202000048 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310645689 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Deutsche Pharmazeutische Gesellschaft. | ||
| 520 | |a A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 µM, followed by 8c (IC50 = 5.12 µM), compared with the standard drug, orlistat (IC50 = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a-f and 8a-f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of -163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π-π stacking and π-cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides (8a-d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization | ||
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| 650 | 4 | |a molecular dynamics | |
| 650 | 4 | |a orlistat | |
| 650 | 4 | |a pancreatic lipase | |
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| 700 | 1 | |a Paul, Atish T |e verfasserin |4 aut | |
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