Estudos de modelagem molecular dos mecanismos de afinidade relativa para quatro galantamínicos com potencial anti-Alzheimer

Abstract

Alzheimer's disease is currently a serious public health and economic problem stemming from the increased life expectancy of the world's population, which results in complicated psychological symptoms in people with this disease and reflects on devastating social effects on their friends and family. These characteristics result in the redirection of part of the attention of the scientific community to the planning of strategies that seek to decrease or to cease these effects. One of these strategies focuses on the cholinergic system of neurotransmission, searching to inhibit acetylcholinesterase and consequently increase the concentration of acetylcholine in the synaptic space. This allows the neural signal to be prolonged in cases of damage to neurons in neurodegenerative diseases. A natural inhibitor of this enzyme, galantamine, is especially promising. Two galantaminics derivatives, sanguinine and lycoramine, chemically differ from this, respectively, only by a methoxy-hydroxy substitution and a sp2-sp3 binding change. These compounds, however, show very different and opposite modifications in the original inhibitory activity. The simple structural analysis of rigid structures does not reveal the mechanisms by which such subtle chemical distinctions result in such drastic affinity differences. Here, we use computational modeling and molecular dynamics methods to better access the molecular factors of such distinctions. To verify the cumulative effects associated with such substitutions, a hybrid ligand of lycoramine and sanguinine was also modeled. The results suggest that the differences in the mobility of the non-aromatic ring present in lycoramine (with the sp2-sp3 modification) imply a greater ease of hydration of this ligand in solution, in addition to drastic conformational, vibratory and entropic penalties in the binding compared to galantamine. In turn, the possibility of establishing a hydrogen-bonds network adds enthalpic advantages for sanguinine binding. Cumulative effects of the studied modifications are observed with hybrid ligand analyzes. These results, while suggesting an affinity ranking in line with the literature, also suggest ideas that we hope will be useful in more rational planning of anti-Alzheimer's drugs