Análise in silico da interação entre a bomba de efluxo ACRABTOLC e inibidores

Abstract

Efflux pumps are an important defense mechanism that bacteria use to evade antibiotic treatment methods used in medicine to treat infectious diseases. For many years, research groups have been developing new drugs in order to change the current scenario of multiresistance that these microorganisms present, making it difficult for patients to improve. AcrAB-TolC is a protein complex belonging to the RND family, with important distribution in bacteria classified as priority agents for the development of combat methods. Studies using efflux pump inhibitor molecules have been developed as an alternative method to combat multiresistant bacteria. The basis of these inhibitors is the enhancement of existing antibiotic methods. Thus, this study aims to perform ab initio analysis of the interaction of MBX2319 inhibitors and their derivatives with the AcrAB-TolC complex, through quantum mechanics calculations, using the Density Functional Theory (DFT). The calculations of the interaction energies of the involved residues were made using the Molecular Fragmentation with Conjugate Caps (MFCC). The results presented demonstrate the presence of hydrogen bonding that enhances the strength of interaction between ligands analyzed in the AcrAB-TolC complex. Furthermore, the Phe178 residue presented significant results in the 3 analyzed ligands, highlighting its importance for the total energy of interaction. As the main residues involved in the binding of AcrAB-TolC with the antibiotic minocycline, used for comparative analysis, we have ILe277, Phe178, Gly179, Phe615, Arg620, Glu273, Asn274, Leu177 and Ser48. As for the MBX2319 linker, the main residues were Phe178, Phe628, Val139, Phe610, Phe136, Phe615, Tyr327, Val612 and Phe617. Finally, the MBX3132 linker, derived from MBX2319, had as main residues Phe178, Phe628, Phe615, Phe136, Phe610, Val612, Tyr327, ALa286 and ILe277. With these results, we can understand how to improve the treatment methods used to help combat the action of this bacterial resistance mechanism, and thus give light to future research.