Molecular Modeling Study of 2–Substituted Isoindoline Derivatives of α–Amino Acids as Inhibitors of Lipoxygenase by Docking Simulations
Teresa Mancilla Percino,1* José Correa Basurto,2,3,4 Karla S. Alavés Carbajal,2 Nagchielli Valle–Sandoval,2 and José Trujillo Ferrara2,3,4
1 Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Departamento de Química. Apartado Postal 14–740, CP 07000, México, D. F. México. *Responsible author: tmancill@cinvestav.mx
2 Instituto Politécnico Nacional, Escuela Superior de Medicina, Sección de Estudios de Posgrado e Investigación.
3 Departamento de Bioquímica, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomás, Delegación Miguel Hidalgo, C. P. 11340, México, D. F.
4 Departamento de Farmacología. Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomás, Delegación Miguel Hidalgo, C. P. 11340, México, D. F.
]]>Received October 24, 2008
Accepted January 23, 2009
Abstract
In this work two series of isoindolines 1(a–g) and 2(a–g) were evaluated as possible inhibitors of lipoxygenase (LOX) by docking studies, as well as for the antiinflammatories isoindolilamides 3–5 and ibuprofen 6, as part of a theoretical study to found dual LOX/ COX inhibitory activities. Therefore, dihydrodimethylbenzofurane 7, licofelone 8 and darbufelone 9 were also evaluated, which are well–known as dual LOX/COX inhibitors and consequently, in this work they were used to identify their binding sites on the LOX and compared with those obtained from 1(a–g), 2(a–g) and 3 to 6 under study. Analysis of the results showed that all compounds under study could inhibit to the LOX, since they are binding in the same or close to the region as the compounds 7–9 taken as references. Several interactions of heteroatom of all compounds with the amino acid residues of binding sites of LOX were determined. The ΔG values were obtained for all the complexes (LOX–compound), among all the complexes, LOX–8 (–12.76 kcal/mol) resulted to be the most stable; and from the compounds under study, LOX–1f (–8.97 kcal/mol) resulted to be more stable than the other compounds tested. Whereas, theoretical dissociation constant values Kd (µM) were obtained. Among all compounds, 8 (0.000433 µM) showed more affinity to LOX; while from compounds under study, 1f (0.266 µM) exhibited more affinity to LOX. These results also show that compounds 1(a–g) and 2(a–g), and 3–6 could have a dual LOX/COX/ inhibition, as have been shown for 7–9 and from their similar docking study within the COX–1 and COX–2 previously reported.
Key words: Lipoxygenase, Docking, Isoindolines, Antiinflamatory, analgesic, α–Amino acids.
Resumen
En este trabajo se evaluaron dos series de isoindolinas 1 (a–g) y 2(a–g) como posibles inhibidores de lipoxigenasa (LOX) por estudios docking, así como para los antiinflamatorios isoindolilamides 3–5 e ibuprofeno 6, como parte de un estudio para encontrar actividades inhibitorias duales LOX/COX. Además, también fueron evaluados dihidrodimetilbenzofurano 7, licofelona 8 y darbufelona 9, los cuales son bien conocidos como inhibidores duales LOX/COX y consecuentemente, en este trabajo fueron usados para identificar sus sitios de enlazamiento sobre la LOX y comparados con aquellos obtenidos de los compuestos bajo estudio 1(a–g), 2(a–g) y 3 a 6. El análisis de los resultados muestra que los compuestos bajo estudio podrían inhibir a la LOX, dado que actúan en la misma región o cerca que los compuestos 7–9 usados como referencia. Se determinaron algunas interacciones de los heteroátomos de todos los compuestos con los residuos de los aminoácidos de los sitios activos de LOX. Se obtuvieron los valores de ΔG para todos los complejos (LOX–compuestos), entre todos los complejos, LOX–8 (–12.76 kcal/mol) resultó ser el más estable; y de los compuestos bajo estudio, LOX–1f (–8.97 kcal/mol) resultó ser más estable que los otros compuestos probados. Además, se obtuvieron los valores de las constantes de disociación teórica Kd (µM). Entre todos los compuestos, 8 (0.000433 µM) mostró mayor afinidad a la LOX; mientras que de los compuestos bajo estudio, 1f (0.266 µM) exhibió mayor afinidad a la LOX. Estos resultados muestran que los compuestos 1(a–g), 2(a–g) y 3 a 6 podrían tener inhibición LOX/COX dual como ha sido mostrado por 7–9 y del estudio similar docking en COX–1 y COX–2 previamente reportado.
]]> Palabras claves: Lipoxigenasa, Docking, isoindolinas, antiinflamatorio, analgésico, α–Aminoácidos.
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Acknowledgments
Authors thank COFFA, SIP–IPN and for scholarship to K. S.A.C. and also Consejo Nacional de Ciencia y Tecnología (Conacyt– México) for financial support.
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