Diseño in Silico de nuevos bioisósteros de Keterolaco como agentes antiinflamatorios con menor efecto gastrolesivo
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Date
2024
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Universidad Nacional de Trujillo
Abstract
El presente estudio se centra en obtener agentes antiinflamatorios con menores efectos
grastrolesivos. Por lo que, a partir de la molécula de ketorolaco, un antiinflamatorio no
esteroide (AINE), se diseñaron 42 bioisósteros, a los que se determinaron los parámetros
fisicoquímicos (peso molecular, área superficial polar y lipofilicidad) con SwissADME; para
la predicción de la actividad se utilizó el servidor Way2Drug; se realizó un análisis 2D QSAR
cuantificando la actividad antiinflamatoria de los derivados utilizando la base de datos
ChemBL; y para el Modelamiento Molecular se utilizó el archivo 5IKR de la base de datos
Protein Data Bank (PDB), y los parámetros de Autodock Vina. Por último, a la molécula que
cumple con las mejores condiciones se determinó sus parámetros farmacocinéticos. De los
42 derivados de Ketorolaco, 12 moléculas demostraron una buena absorción oral predictiva,
de ellas, 8 moléculas demostraron tener menos efectos gastrolesivos con Way2Drug y, bajo
el análisis 2D QSAR se demostró que 3 tenían una muy buena actividad antiinflamatoria.
Las moléculas 32 y 34 inhibieron adecuadamente la enzima COX-2, pero la molécula 32
mostró un mayor efecto antiinflamatorio y analgésico con menos efectos secundarios. Esta
molécula es sustrato de CYP3A4 y CYP1A2 y se elimina por N-glucoronidación renal. Las
dosis orales tóxica aguda y crónica son altas, posiblemente debido a la presencia de
metilsulfonamida o el aromático libre. En conclusión, la molécula 32 tiene un alto potencial
para ser un candidato a fármaco seguro, sin embargo, se necesitan estudios preclínicos y
otros para confirmar estos hallazgos.
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.
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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Keywords
Ketorolaco, In silico, Diseño de fármacos, Bioisósteros, Antiinflamatorio