Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations
Por:
Cano-González L., Espinosa-Mendoza J.D., Matadamas-Martínez F., Romero-Velásquez A., Flores-Ramos M., Colorado-Pablo L.F., Cerbón-Cervantes M.A., Castillo R., González-Sánchez I., Yépez-Mulia L., Hernández-Campos A., Aguayo-Ortiz R.
Publicada:
1 ene 2023
Resumen:
Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of a/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an a-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity. © 2023 American Chemical Society
Filiaciones:
Cano-González L.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Espinosa-Mendoza J.D.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Matadamas-Martínez F.:
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico
Romero-Velásquez A.:
Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Flores-Ramos M.:
Escuela Nacional de Estudios Superiores, Unidad Merida, Universidad Nacional Autonoma de Mexico, Yucatan, 97357, Mexico
Colorado-Pablo L.F.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Cerbón-Cervantes M.A.:
Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Castillo R.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
González-Sánchez I.:
Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Yépez-Mulia L.:
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico
Hernández-Campos A.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Aguayo-Ortiz R.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
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