Design,synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating α-asarone-based HMG-CoA reductase inhibitors |
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Authors: | Nancy Argüelles Eugenia Sánchez-Sandoval Aarón Mendieta Lourdes Villa-Tanaca Leticia Garduño-Siciliano Fabiola Jiménez María del Carmen Cruz José L Medina-Franco Germán Chamorro-Cevallos Joaquín Tamariz |
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Institution: | 1. Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala s/n, 11340 México, D.F., Mexico;2. Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico;3. Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Sta. Inés Km 1.5, Tepetitla, 90700 Tlaxcala, Mexico;4. Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico;5. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA |
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Abstract: | A series of α-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of α-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity. |
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