Estudos in silico da formação de complexos de alguns fármacos relacionados com a obesidade e potenciais receptores-alvo

Abstract

Obesity is a global health problem in the most diverse geographic locations at all socioeconomic levels that affects several physiological functions and increases the risk of cardiovascular diseases, tumors, musculoskeletal and mental disorders. Some anorectic or appetite-reducing drugs have been administered to promote the reduction of body mass index and to control the obesity. Within this context, a major challenge has been to identify the formation of new complexes ligand-receptor associated with possible positive effects on the improvement of the obese state. Thus, the present study aimed to investigate in silico the formation of complexes of the ligands mazindol, sibutramine and melatonin, drugs related to control and prevention of the obesity, and their potential receptors targeted by molecular docking analyses. The different steps established in this experimental procedure were grouped into three main axes: a) search and selection of 3D structures of the drugs of interest from database DrugBank; b) search and selection of 3D structures of potential protein sequences of receptor-targeted using STRING, protein BLAST, and database PDB; and c) characterization of the formation of the complexes between ligands of interest and receptor-targeted using AutoDock4.0 server by molecular docking analyses. Among all drugs tested in the present study, high reliability score and significant similarity were only identified between type 1B melatonin and alpha-2A adrenergic receptors. Thus, molecular docking assays were carried out using ligand melatonin and crystallographic structures of the alpha-2A adrenergic receptor coupled to an antagonist (ID PDB 6kux) and a partial agonist (ID PDB 6kuy) available in the database PDB. In silico results demonstrated values of binding energy of -6.79 and -6.98 kcal/mol for 6kux and 6kuy adrenergic receptors, respectively. Furthermore, the presence of non-covalent intermolecular interactions, such as hydrogen bonds and hydrophobic interactions, were revealed in the formation of complexes between melatonin and both alpha-2A adrenergic receptors of interest. Preliminary experimental findings described in the literature have revealed a possible interaction of the neurohormone melatonin to adrenergic receptors, indicating its ocular hypotensive effects in rabbits. The findings predicted in the present study suggest the formation of complexes between melatonin and alpha-2A adrenergic receptor by molecular docking analyses, showing satisfactory energy values and structural stability by non-covalent intermolecular interactions. Based on the preliminary data predicted in this study, additional procedures must be established to ensure the experimental validation of the complex melatonin-alpha 2A adrenergic receptor, as well as to test the biological viability of this interaction ligand-receptor of interest and its positive effects on the improvement of the obese state.