Bibliographic citations
Gamarra, C., (2024). Diseño in Silico de nuevos bioisósteros de Keterolaco como agentes antiinflamatorios con menor efecto gastrolesivo [Universidad Nacional de Trujillo]. https://hdl.handle.net/20.500.14414/21536
Gamarra, C., Diseño in Silico de nuevos bioisósteros de Keterolaco como agentes antiinflamatorios con menor efecto gastrolesivo []. PE: Universidad Nacional de Trujillo; 2024. https://hdl.handle.net/20.500.14414/21536
@phdthesis{renati/1046333,
title = "Diseño in Silico de nuevos bioisósteros de Keterolaco como agentes antiinflamatorios con menor efecto gastrolesivo",
author = "Gamarra Sánchez, César Demófilo",
publisher = "Universidad Nacional de Trujillo",
year = "2024"
}
The present study aimed to obtain anti-inflammatory agents with fewer gastro-injurious effects. Therefore, from the ketorolac molecule, a non-steroidal anti-inflammatory drug (NSAID), 42 bioisosteres were designed, for which the physicochemical parameters (molecular weight, polar surface area and lipophilicity) were determined with SwissADME; The Way2Drug server was used to predict activity; A 2D QSAR analysis was performed quantifying the anti-inflammatory activity of the derivatives using the ChemBL database; and for Molecular Modeling, the 5IKR file from the Protein Data Bank (PDB) database was used, and the Autodock Vina parameters. Finally, its pharmacokinetic parameters were determined for the molecule that meets the best conditions. Of the 42 Ketorolac derivatives, 12 molecules demonstrated good predictive oral absorption, of them, 8 molecules demonstrated less gastro-injurious effects with Way2Drug and, under 2D QSAR analysis, 3 were shown to have high anti-inflammatory activity. Molecules 32 and 34 adequately inhibited the COX-2 enzyme, but molecule 32 showed a greater anti-inflammatory and analgesic effect with fewer side effects. This molecule is a substrate of CYP3A4 and CYP1A2 and is eliminated by renal N-glucuronidation. Acute and chronic toxic oral doses are high, possibly due to the presence of methylsulfonamide or the free aromatic. In conclusion, molecule 32 has a high potential to be a safe drug candidate, however, preclinical, and other studies are needed to confirm these findings.
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