TRIAGEM VIRTUAL DE COMPOSTOS ANÁLOGOS A FÁRMACOS INIBIDORES DE RECAPTAÇÃO DE SEROTONINA COMO POSSÍVEIS ANTICOLINESTERÁSICOS

Abstract

Clinically, Alzheimer's disease (AD) is associated with functional and behavioral symptoms, in addition to several cognitive symptoms, which can be explained by the cholinergic neurotransmission deficit. Galantamine, an acetylcholinesterase (AChE) inhibitor compound, has been widely used as the main treatment for AD. Clinical evidence and imaging studies suggest that patients treated with the anticholinesterase inhibitor galantamine in conjunction with antidepressants in the Selective Serotonin Reuptake Inhibitor (SSRI) class may experience additional benefit. Major Depressive Disorder (MDD) currently affects over 350 million people globally. Newer drugs for treating this disorder were approved for use in the late 2000s, among which are the SSRIs. Considering the possible use of SSRIs as anticholinesterases, the present study aims to evaluate the inhibitory character of molecules of natural origin, with chemical structures similar to those from the antidepressants fluoxetine, sertraline, escitalopram and vortioxetine, against the AChE enzyme. A virtual screening was performed based on the substructures of the mentioned antidepressants, in the PubChem, Natural Products Atlas and Drug Bank databases. The compounds that complied with Lipinski's Rule of Five, showed no toxicity and demonstrated a satisfactory LD50 value, underwent the molecular docking protocol. The data obtained revealed the presence of four possible inhibitors: (2'S,11bR)-variecolortin B, (1aR,1bS,6aR,7aR,7bS,11aS)-spiroxin E, (2'R,5'Z,11bR)-variecolortin B and (1aR,1bS,6aS,7aR,7bS,11aS)-spiroxin B. All intermolecular interactions evaluated occurred between compounds and residues, such as Trp-286, Phe-297 and Ser-293, already proven in the literature as present in the active site of the AChE enzyme. However, they showed a slightly lower binding affinity to the enzyme site than the reference inhibitor. All compounds exhibited physicochemical properties favorable to oral bioavailability. These are potential agents for planning and developing new drugs and/or treatments for AD. As this is an in silico study, it is advisable to evaluate it in in vitro tests and, subsequently, in vivo, to determine its real effectiveness.