Avaliação do potencial de ação do Carvacrol e seus análogos sobre receptores da Colecistocinina visando a modulação da dor trigeminal: um estudo in silico

Abstract

Trigeminal pain (TP), characterized as neuropathic pain, significantly affects the patient's quality of life due not only to its inherent condition but also to the side effects of various drugs used in its management. TP presents different etiologies and characteristics, complicating its treatment and often resulting in only partial pain relief. Natural products, such as carvacrol (CV), have shown promise in pain management. This study aimed to perform virtual screening of bioactivity and molecular docking simulations of CV analogs on cholecystokinin (CCK) receptors, targeting the modulation of trigeminal pain. Initially, a virtual screening of the bioactivity of CV and its synthetic derivatives, CV aldehyde, CV Schiff base (BSCV), and Schiff base-Copper Complex (BSCu²⁺), was conducted. This screening corresponded to the combination of up to 20 of the most stable conformations of the input compound and the 20 most stable conformations deposited in the European Molecular Biology Laboratory (ChEMBL) database, which exhibit known biological activity against Mus musculus and Rattus norvegicus. Subsequently, an absorption, distribution, metabolism, and excretion (ADME) study was carried out, including analyses of molecular lipophilicity potential, MPO and lipophilicity-metabolism efficiency (LipMetE) analyses, and prediction of the site of metabolism and acute toxicity for M. musculus and R. norvegicus. Finally, molecular docking simulations were performed targeting CCK1 and CCK2 receptors. The virtual evaluation of the structures revealed that synthetic CV analogs have promising potential for treating peripheral and neural disorders due to their structural similarity to other compounds affecting CCK1 and CCK2 receptors in the central (CNS) and peripheral nervous systems. Additionally, the ADME analysis, focusing on MPO, indicated a comprehensive distribution of these substances throughout the CNS and peripheral nervous systems, particularly BSCu²⁺, which showed a more favorable correlation between pharmacokinetic properties and CNS activity safety. However, BSCV exhibited high passive permeability and a broad volume of distribution in the brain. Despite this, this ligand also demonstrated more positive pharmacodynamic interaction with the CCK2 receptor, making it promising for chronic pain treatment. Based on the collected data, it is hypothesized that synthetic carvacrol analogs, BSCu²⁺ and BSCV, as potential CCK2 receptor antagonists present in the neurons of trigeminal and spinal ganglia, can compete with CCK, enhancing the effect of opioids in trigeminal pain management. Although this hypothesis remains unresolved, the results obtained through computational modeling open new avenues for understanding the potential mechanisms of action of carvacrol analogs in modulating trigeminal pain, providing insights for research in animal models aimed at validating this proposition.