Pharmacophore modeling, molecular docking, and molecular dynamics studies to identify new 5-HT 2A R antagonists with the potential for design of new atypical antipsychotics.

Some important atypical antipsychotic drugs target the serotonergic receptor 2A (5-HT 2A R). Currently, new therapeutic strategies are needed to offer faster onset of action with fewer side effects and, therefore, greater efficacy in a substantial proportion of patients with neuropsychological disorders such as Autism and Parkinson. The main objective of this work was to use SBDD methods to identify new hit compounds potentially useful as precursors of novel and selective 5-HT 2A R antagonists. A structure-based pharmacophore screening study based on a selective antagonist was carried out in ten databases. The set obtained was refined using molecular docking, and the five most promising compounds were subjected to molecular dynamics simulations. The most stable and promising hit occupied a side pocket present in the 5-HT 2A R, a site that can be explored to obtain selective ligands. Simulations against 5-HT 2C R and D 2 R showed that the best hit could not form stable complexes with these targets, strengthening the hypothesis that the hit presents selective binding by the receptor of interest. The selected hits showed some predicted toxicity risk or violated some drug-likeness property. However, it can be concluded that the identified hits are the most promising for performing in vitro assays. Once the presence of activity is confirmed, they could become precursors of optimized and selective antagonists of 5-HT 2A R. An SBDD study was carried out to identify new selective 5-HT 2A R ligands potentially useful for designing selective atypical antipsychotics.