Química computacional aplicada ao estudo do potencial modulatório sobre adenosina a1 de alcaloides carbazólicos

Abstract

Parkinson's disease (PD) belongs to the class of neurodegenerative diseases because it induces irreversible damage to the brain structure through the oxidation of neurotransmitters that are essential for its functioning. PD, specifically, is characterized by causing motor symptoms such as tremors and muscle stiffness in affected patients. Despite existing therapies based on monoamine oxidase B inhibitors, researchers have revealed a strong correlation between adenosine A1 and A2AR receptors in inhibiting the ion reuptake effect and intracellular striatal dopamine observed in rats. In this premise, carbazomicins are pharmacophores claimed for elaborating active substances in the central nervous system (CNS) with promising therapeutic effect, since they are carbazole derivatives reported in neural anti-inflammatory activity and neuroprotective activity. Thus, this study aims to explore the structural, electronic and modulatory bioactivity properties of adenosine A1 receptors of a series of substituted carbazomicin derivatives (CCB1-4). For this purpose, a structural optimization at the quantum level by Density Functional Theory (DFT) was performed to analyze their global reactivity descriptors. At the same time, a structure-based virtual screening approach was used to conduct molecular docking and molecular dynamics simulations of CCB1-4 derivatives in complex with the adenosine A1 receptor. The results showed that the difference in different environments (water, DMSO and chloroform) does not drastically affect the reactivity of CCB1-4 derivatives, as seen by DFT calculations using the 6-31++G(d,p) double-ζ base. The target prediction test, guided by the structure-based virtual screening strategy, showed that the heteroaromatic nature of CCB1-4 leads to structural similarity with other nitrogenous bases modulating A1R receptors, including the endogenous ligand adenosine (ADN). Thus, molecular docking simulations estimated a higher affinity of the CCB3 derivative to the receptor, with a calculated value of -8.6 kcal/mol, when binding to the DNA agonist site. Corroborating this, molecular dynamics simulations showed that the compound stably binds to the target, with a binding free energy of approximately -25.9 kcal/mol. These results suggest that CCB3 can antagonize DNA binding to its receptors, an effect associated with A1R modulators in treating PD.