A busca de fármacos úteis no tratamento do autismo: estudos in silico para identificação de novos ligantes seletivos do receptor 5-HT2A

Abstract

Serotonin (5-HT) receptors are part of a family, the 5HT2 subfamily is divided into 2A, 2B and 2C receptors. The 2A receptor has high affinity for the atypical antipsychotic drugs clozapine, risperidone, and olanzapine and is believed to play a role in the therapeutic activity of these drugs. Currently, new therapeutic strategies are needed that offer faster onset of action with fewer side effects and, therefore, greater efficacy in a greater proportion of patients with neuropsychological disorders. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication, as well as the presence of restricted or repetitive behaviors and interests. Currently, several therapeutic targets have been described as associated with main or peripheral symptoms of this framework. However, so far, the few drug interventions aim to control certain associated symptoms, such as seizures, anxiety, irritation, lack of sleep, and others. In most cases, these are drugs commonly used in neuropsychiatry, such as anxiolytics, anticonvulsants, etc., used off-label, such as risperidone. Risperidone primarily targets the 5-HT2AR and D2R receptors, where it acts as an antagonist. However, this drug, although useful (or potentially useful), was originally and specifically developed for the treatment of autistic people. Thus, this work had as main objective to study a set of compounds selected from the literature, which were used in the identification of hit compounds possible candidates for antipsychotics that act as 5-HT2A receptor blockers. Based on these sets, computer-aided drug planning studies were carried out (molecular modeling, structure-activity relationship, pharmacophoric modeling and virtual screening), in addition to Molecular Dynamics simulation studies. The approach used led to the identification of compounds that were shown, in the DM simulations, to be stable at the binding site, capable of maintaining interactions with amino acid residues important for inhibition, similarly to risperidone. These results indicate a possibility that these compounds exhibit an antagonistic effect on the 5HT2A receptor. These compounds then become candidates for biological tests aiming at confirming the results obtained.