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Acoplamiento molecular entre fármacos para Alzheimer y la enzima γ-secretasa.
Molecular Docking between Alzheimer's Drugs and γ-secretase Enzyme
Acoplamento molecular entre medicamentos para Alzheimer e a enzima γ-secretase
DOI:
https://doi.org/10.15446/rev.colomb.quim.v53n2.117655Palabras clave:
acoplamiento molecular, diseño de fármacos, enfermedad de Alzheimer, y-secretasa, presenilina 1 (es)Molecular docking, drug design, Alzheimer's disease, γ-secretase, presenilin 1 (en)
acoplamento molecular, concepção de medicamentos, doença de Alzheimer, γ-secretase, presenilin 1 (pt)
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La enfermedad de Alzheimer (EA) es la forma más común de demencia y consiste en un deterioro cognitivo y conductual que afecta principalmente a los adultos mayores. Se estima que, en los próximos 30 años, 115 millones de personas en todo el mundo estarán afectadas por esta enfermedad. Ante el aumento previsto de casos, los investigadores están buscando alternativas para controlar la EA. Un enfoque importante es el estudio de la proteína γ-secretasa, relacionada con la neurotoxicidad de los péptidos involucrados en la cascada amiloide, una vía bioquímica fundamental en el desarrollo de la EA.
En este trabajo se realizaron estudios in silico con los fármacos JNJ-40418677, GSM-1, bexaroteno y trodusquemina para evaluar su eficacia como moduladores del sitio activo de la subunidad catalítica presenilina 1 (PSEN-1), que forma parte del complejo γ-secretasa. Según los valores de energía de afinidad obtenidos en el acoplamiento molecular, JNJ-40418677 fue identificado como el compuesto con mayor potencial de unión a PSEN-1, seguido de trodusquemina, bexaroteno y GSM-1. Los resultados obtenidos aportan información relevante sobre las características químicas y físicas básicas que deberán ser consideradas en el diseño de moléculas con potencial inhibitorio sobre la γ-secretasa que, como consecuencia, tendrían implicaciones en el tratamiento de la EA.
Alzheimer's disease (AD) is the most common form of dementia, characterized by cognitive and behavioral decline, and primarily affects older adults. It is estimated that worldwide, 115 million people will be affected by the disease in the next 30 years. Given the anticipated increase in cases, researchers are exploring various alternatives to control AD. One area of focus is the study of the γ-secretase protein, which is linked to peptide neurotoxicity involved in the amyloid cascade, a key biochemical pathway in the development of AD.
In this study, in silico studies were conducted with the drugs JNJ-40418677, GSM-1, bexarotene, and trodusquemine to evaluate their efficacy as modulators of the active site of the presenilin catalytic subunit 1 (PSEN-1), which is part of the γ-secretase complex. According to the affinity energy values obtained from molecular docking, JNJ-40418677 was identified as the compound with the greatest binding potential to PSEN-1, followed by trodusquemine, bexarotene, and GSM-1. The results obtained provide relevant information on the basic chemical and physical characteristics that should be considered in the design of molecules with inhibitory potential on γ-secretase, which, as a result, would have implications for the treatment of AD.
A doença de Alzheimer (DA) é a forma mais comum de demência e consiste em comprometimento cognitivo e comportamental, que afeta principalmente adultos mais velhos. Estima-se que, nos próximos 30 anos, 115 milhões de pessoas em todo o mundo serão impactadas pela doença. Diante do aumento previsto de casos, pesquisadores estão investigando diversas alternativas para o controle da DA. Um dos focos de estudo é a proteína γ-secretase, associada à neurotoxicidade dos peptídeos envolvidos na cascata amiloide, uma via bioquímica crucial para o desenvolvimento da DA.
Neste estudo, realizamos análises in silico com os medicamentos JNJ-40418677, GSM-1, bexaroteno e trodusquemina, visando avaliar sua eficácia como moduladores do sítio ativo da subunidade catalítica presenilina 1 (PSEN-1), parte do complexo γ-secretase. De acordo com os valores de energia de afinidade obtidos na metodologia de acoplamento molecular, o fármaco JNJ-40418677 foi identificado como o que apresenta o maior potencial de ligação com a subunidade PSEN-1, seguido pela trodusquemina, bexaroteno e GSM-1. Os resultados obtidos fornecem informações relevantes sobre os primeiros passos no design de moléculas com potencial inibitório sobre a γ-secretase o que, como consequência, teriam implicações no tratamento da EA.
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Derechos de autor 2025 Ana Paola Jara y Rivera, Andrea Moreno Ceballos, María Eugenia Castro, Francisco J. Melendez, Norma A. Caballero
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