Interação in silico de derivados curcuminoides sintéticos com a proteína da obesidade associada à massa gorda (FTO)

Abstract

Obesity is one of the diseases that has gained the most notoriety in recent times, affecting millions of people worldwide. Most of the pharmacological options offered today as treatment, generate unwanted adverse effects to the patient, and can even, in high doses, compromise their health in an irreversible way. In this context, as they develop fewer adverse effects to the patient, and have a high antioxidant power, curcuminoids have been studied as potential substances with anti-obesity action. The objective of the present work was to study the theoretical interaction of seven synthetic curcuminoids – DBACETONE, DBANISALDEHYDE, DBCINAMALDEHYDE, DBCHLORINE, DBCYAN, DBTOXIDE and DBTHIOPHENE – structurally similar, differing only in the type of aromatic ring attached to the chain, in the number of carbons present in the chain. and in the functional groups linked to the rings, with the obesity protein associated with fat mass – FTO. The crystallographic structure of the target molecule was obtained from the Protein Data Bank database and the curcuminoid derivatives and the inhibitor drug chosen as reference, orlistat, were designed and optimized in Avogadro software for subsequent molecular docking on the SwissDock online server. The results were visualized and evaluated using the USCF Chimera and BIOVIA Discovery Studio programs. The synthetic curcuminoids showed favorable Gibbs free energy values showing thermodynamic potential for a significant interaction with FTO. It was observed that some of the curcuminoid derivatives and the drug orlistat showed interaction at the same binding site, demonstrating inhibitory potential. Different intermolecular interactions were found for the synthetic derivatives and the reference drug, proving their interactions with the macromolecule, among them: hydrogen bond, π – cation, π – alkyl, alkyl, π – π T-shaped, π – hydrogen bond and covalent bond. Different amino acid residues showed in this study the interaction of FTO protein with synthetic curcuminoids, especially HIS305, LEU285, PRO283, TRP42 and GLN41 – orlistat inhibitory active site and coupling region of other candidate molecules tested. In conclusion, all synthetic curcuminoids showed interaction with FTO, showing low values of Gibbs free energy. Among them, DBANISALDEHYDE was the most prominent molecule. The synthetic derivatives tested here proved to be good candidates for more robust molecular docking studies and subsequent in vitro and in vivo studies.