Derivados de inhibidores de DPP-4 con actividad sobre Mpro SARS-Cov-2: un estudio in silico
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Date
2023
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Universidad Nacional de Trujillo
Abstract
Esta investigación tuvo como objetivo determinar derivados de inhibidores DPP-4 con actividad sobre Mpro SARS-Cov-2. Para lograr este fin, se prepararon bioisósteros de Sitagliptina empleando la base de datos ZINC20, como resultado se obtuvo 50 bioisósteros, de los cuales se seleccionaron 27 por presentar mejor absorción gastrointestinal y no atravesar barrera hematoencefálica, bajo el uso de las herramientas web SwissADME y la gráfica modelo BOILED-egg. Sucesivamente, con Open Babel se realizaron las estructuras 3D de los ligandos, se agregaron hidrógenos polares y cargas a pH fisiológico 7,4. La estructura cristalina de la proteasa Mpro de SARS-Cov-2 se obtuvo de la Base de Datos de Proteínas (Protein Data Bank – PDB) bajo el código 7BB2, que fue tratada previamente con el programa PyMOL y parametrizada usando AutoDock Tools. La realización del docking molecular fue bajo el empleo algoritmo Autodock Vina; así mismo, las posiciones de acoplamiento vinculantes se inspeccionaron utilizando los programas PyMOL y Discovery Studio. Como resultado se encontró que la interacción más favorable la presentó M17 por presentar baja energía de unión y un mayor número de puentes de hidrógeno. Con la constante de inhibición (ki) y la eficiencia del enlace (LE) se encontró que las moléculas M2, M5, M7, M11, M12, M16, M17, M20, M24 y M30 presentan mejor o igual energía de afinidad que el referente, una potencia favorable, pero en la eficiencia del enlace tiene valores entre -0,24 y -0,28. Adicionalmente, el análisis de las propiedades farmacocinéticas se realizó en pkCSM, evidenciándose que M5 tiene la capacidad de inhibir el transporte de P-gp I y P-gp II P. M5 es sustrato de la CYP3A4; sumado a esto se observa qué M5 y M17 son sustrato de CYP3A4, M5 además inhibe CYP2C19. El clearence para M5 y M17 presenta un valor log ml/min/kg de 0,348 y 0,204 respectivamente, considerado aceptable. Finalmente, a excepción de M30, ninguna de las moléculas es sustrato del transportador de catión orgánico 2 (OCT2) renal, ni tampoco da positivo al test de AMES.
ABSTRACT This research aimed to determine derivatives of DPP-4 inhibitors with activity on Mpro SARS-Cov-2. To achieve this purpose, bioisosteres of Sitagliptin were prepared using the ZINC20 database, as a result, 50 bioisosteres were obtained, of which 27 were selected for presenting better gastrointestinal absorption and not crossing the blood-brain barrier, using the SwissADME web tools and the BOILED-egg model graph. Subsequently, with Open Babel, the 3D structures of the ligands were made, polar hydrogens and charges were added at physiological pH 7.4. The crystal structure of the SARS-Cov-2 protease Mpro was obtained from the Protein Database (Protein Data Bank – PDB) under the code 7BB2, which was previously treated with the PyMOL program and parameterized using AutoDock Tools. The molecular docking was carried out using the Autodock Vina algorithm; Likewise, the binding docking positions were inspected using the PyMOL and Discovery Studio programs. As a result, it was found that the most favorable interaction was presented by M17 due to its low binding energy and a greater number of hydrogen bonds. With the inhibition constant (ki) and the binding efficiency (LE), it was found that the molecules M2, M5, M7, M11, M12, M16, M17, M20, M24 and M30 present better or the same affinity energy than the reference. , a favorable power, but in the link efficiency it has values between -0.24 and -0.28. Additionally, the analysis of the pharmacokinetic properties was carried out in pkCSM, showing that M5 has the ability to inhibit the transport of P-gp I and P-gp II P. M5 is a substrate of CYP3A4; Added to this, it is observed that M5 and M17 are substrates of CYP3A4, M5 also inhibits CYP2C19. The clearance for M5 and M17 presents a log ml/min/kg value of 0.348 and 0.204 respectively, considered acceptable. Finally, with the exception of M30, none of the molecules is a substrate of the renal organic cation transporter 2 (OCT2), nor does it test positive in the AMES test.
ABSTRACT This research aimed to determine derivatives of DPP-4 inhibitors with activity on Mpro SARS-Cov-2. To achieve this purpose, bioisosteres of Sitagliptin were prepared using the ZINC20 database, as a result, 50 bioisosteres were obtained, of which 27 were selected for presenting better gastrointestinal absorption and not crossing the blood-brain barrier, using the SwissADME web tools and the BOILED-egg model graph. Subsequently, with Open Babel, the 3D structures of the ligands were made, polar hydrogens and charges were added at physiological pH 7.4. The crystal structure of the SARS-Cov-2 protease Mpro was obtained from the Protein Database (Protein Data Bank – PDB) under the code 7BB2, which was previously treated with the PyMOL program and parameterized using AutoDock Tools. The molecular docking was carried out using the Autodock Vina algorithm; Likewise, the binding docking positions were inspected using the PyMOL and Discovery Studio programs. As a result, it was found that the most favorable interaction was presented by M17 due to its low binding energy and a greater number of hydrogen bonds. With the inhibition constant (ki) and the binding efficiency (LE), it was found that the molecules M2, M5, M7, M11, M12, M16, M17, M20, M24 and M30 present better or the same affinity energy than the reference. , a favorable power, but in the link efficiency it has values between -0.24 and -0.28. Additionally, the analysis of the pharmacokinetic properties was carried out in pkCSM, showing that M5 has the ability to inhibit the transport of P-gp I and P-gp II P. M5 is a substrate of CYP3A4; Added to this, it is observed that M5 and M17 are substrates of CYP3A4, M5 also inhibits CYP2C19. The clearance for M5 and M17 presents a log ml/min/kg value of 0.348 and 0.204 respectively, considered acceptable. Finally, with the exception of M30, none of the molecules is a substrate of the renal organic cation transporter 2 (OCT2), nor does it test positive in the AMES test.
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Keywords
Sitagliptina,3CLpro, Mpro, COVID-19, modelado molecular, bioisósteros