Análise por simulação computacional de derivados teóricos da sibutramina

Abstract

Medicinal chemistry is based on chemical and pharmacological knowledge to design and develop new bioactive molecules (drugs) or modify existing ones, promoting innovation in the treatment of diseases. The drugs produce a therapeutic response when interacting with biomacromolecules, presenting biological activity related to its molecular structure. In drug planning, molecular modeling is an insilico tool used for the structural design and optimization of the spatial geometry of molecules, allowing conformational analysis through the length and bonding angle, in addition to graphically represent some properties of molecules, such as the map of electrostatic potential. The molecular docking allows to quantify and qualify the chemical interactions between a binder (drug) and its target (biomacromolecule), identifying the possible sites of interaction. Sibutramine is a tertiary amine belonging to the class of the cycloalkylamines derivatives, having as the basic structure the cyclobutanoethanamine with a stereogenic center. Anti-obesogenic drug derived from amphetamine, sibutramine has affinity for 5-HT2c serotonergic receptors, having as mechanism of action the inhibition of the reuptake of serotonin in presynaptic neurons. The maintenance of serotonin levels in a normal state leads to a feeling of satiety, reason why sibutramine acts to reduce appetite and is used in the treatment of obesity. However, studies show that prolonged use of sibutramine increases the risk of cardiovascular accidents, by increased blood pressure and heart rate. The studied analogs presented lower free energy of bonding with the 5-HT2c receptor than sibutramine. Among them, the analogue 1 was the one that presented the lowest free energy of binding, presenting greater affinity for the biomacromollecule and being able to reduce the adverse effects caused by the drug.