Publication: Modelado molecular como herramienta para el descubrimiento de nuevos fármacos que interaccionan con proteínas
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2017-06
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Abstract
Las enfermedades de Alzheimer y Parkinson constituyen dos ejemplos de trastornos neurodegenerativos del sistema nervioso central (SNC), caracterizados por un proceso crónico y selectivo de muerte neuronal, que se manifiesta con alteraciones de los movimientos, déficit cognitivo y demencia. Se ha demostrado que la inhibición de la Rhokinasa (ROCK) en el SNC promueve la reparación de los tejidos alterados en el Alzheimer, y en el Parkinson protege las neuronas dopaminérgicas y mejora las capacidades de movimiento. Además, la inhibición de la MAO (monoaminooxidasa) lleva indirectamente a un incremento de la transmisión dopaminérgica, esencial en el tratamiento del Parkinson, y reduce la formación de peróxidos, responsables de la formación de radicales libres y del estrés oxidativo celular a nivel de la substancia nigra (fenómeno responsable de la neurodegeneración). Uno de los retos de hoy en día, es la obtención de fármacos multidiana, capaces de interaccionar con más de una macromolécula y cuyo efecto farmacológico derive de la interacción con éstas de forma aditiva o sinérgica. Por eso, nos planteamos diseñar un fármaco multidiana capaz de inhibir tanto la ROCK como la MAO. Para ello, decidimos unir al fasudil, un potente inhibidor de la ROCK, un sustituyente propargílico, fragmento farmacóforo de algunos inhibidores suicidas de la MAO, como la clorgilina y la rasagilina. Antes de plantear la síntesis química, decidimos emplear el docking molecular, una técnica computacional que permite estudiar la interacción entre un ligando y un receptor, mediante el estudio de las energías de enlace entre ambas moléculas. A través de esta técnica, se comparó la interacción del fasudil-propargilo con la interacción del fasudil con la ROCK, la clorgilina con la MAO A y la rasagilina con la MAO B. En los tres casos, el fármaco multidiana resultó tener una afinidad comparable o mejor que la del fármaco de referencia.
The Alzheimer's and Parkinson's diseases are two examples of neurodegenerative disorders of the central nervous system (CNS) characterized by a chronic and selective process of neuronal death manifested by alterations of movement, cognitive deficit and dementia. The Inhibition of Rho-kinase (ROCK) in the CNS has been shown to promote the repair of altered tissues in Alzheimer's disease, and protects dopaminergic neurons and improves movement abilities in Parkinson’s disease. In addition, the inhibition of MAO (monoamine oxidase) leads indirectly to an increase in the dopaminergic transmission which is essential to the treatment of Parkinson's, and reduces the formation of peroxides responsible for the formation of free radicals and cellular oxidative stress at the level of Substance nigra (responsible for neurodegeneration). One of the challenges of today is the production of multidiana drugs capable of interacting with more than one macromolecule, whose pharmacological effect is derived from their interaction in an additive or synergistic way. Therefore, this study aims to design a multidial drug capable of inhibiting both ROCK and MAO. To do this, a Fasudil, a potent inhibitor of ROCK, a propargylic substituent, and a pharmacophore fragment of some MAO suicide inhibitors, such as clorgiline and rasagiline were binded. Before proposing the chemical synthesis, a molecular docking, a computational technique that allows to study the interaction between a ligand and a receptor by studying the binding energies between both molecules was used. Through this technique, the interaction of fasudil-propargyl with the interaction of fasudil with ROCK, clorgiline with MAO A and rasagiline with MAO B was compared. In all three cases, the multidose drug was found to have a comparable affinity, better than that of the reference drug.
The Alzheimer's and Parkinson's diseases are two examples of neurodegenerative disorders of the central nervous system (CNS) characterized by a chronic and selective process of neuronal death manifested by alterations of movement, cognitive deficit and dementia. The Inhibition of Rho-kinase (ROCK) in the CNS has been shown to promote the repair of altered tissues in Alzheimer's disease, and protects dopaminergic neurons and improves movement abilities in Parkinson’s disease. In addition, the inhibition of MAO (monoamine oxidase) leads indirectly to an increase in the dopaminergic transmission which is essential to the treatment of Parkinson's, and reduces the formation of peroxides responsible for the formation of free radicals and cellular oxidative stress at the level of Substance nigra (responsible for neurodegeneration). One of the challenges of today is the production of multidiana drugs capable of interacting with more than one macromolecule, whose pharmacological effect is derived from their interaction in an additive or synergistic way. Therefore, this study aims to design a multidial drug capable of inhibiting both ROCK and MAO. To do this, a Fasudil, a potent inhibitor of ROCK, a propargylic substituent, and a pharmacophore fragment of some MAO suicide inhibitors, such as clorgiline and rasagiline were binded. Before proposing the chemical synthesis, a molecular docking, a computational technique that allows to study the interaction between a ligand and a receptor by studying the binding energies between both molecules was used. Through this technique, the interaction of fasudil-propargyl with the interaction of fasudil with ROCK, clorgiline with MAO A and rasagiline with MAO B was compared. In all three cases, the multidose drug was found to have a comparable affinity, better than that of the reference drug.