Biofísica quântica da ligação de adutos da isoniazida às enzimas redutase do Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is an infectious disease caused by bacillus called Mycobacterium tuberculosis (MT). According to latest data WHO (World Health Organisation), approximately 2 million people die annually worldwide due to tuberculosis and other 9 million are affected each year. However, this disease is curable, and one of the first-line drugs for the treatment of TB is isoniazid (INH). However, during recent years are emerging multi-resistant strains to INH, and to other first-line drugs, known as MDR-TB (Multidrug Resistant Tuberculosis). Thus, the use of molecular modeling he been one of the strategies employed in the study and development of drugs more potent against MDR-TB strains. In this study were carry out theoretical-computational studies concerning to the binding of adducts of isoniazid (INH) to the active site of the reductase protein MT. The first system studied was INADH bioactive compound, a derivative of peroxidase-catalyzed INH, complexed to the reductase enzyme encoded by inhA gene. While the second system consisted of the acyclic 4R isomer of INH (4R-INADP) bound at the active site of dihydrofolate reductase protein, called dfrA. Through the method quantum DFT (Density Functional Theory) applied to MFCC (Molecular Fractionation with Conjugate Caps) approach, were calculated the interaction energies between the bioactive compounds and amino acids of the active site of enzymes. Through the calculations of the interaction energy of the ligands with the active site of enzymes inhA and dfrA, was mapped the energy profile to the interaction of the most important amino acids through the BIRD (Binding site, Interaction energy na Residues Domain) graphic. So it was possible to identify the most active regions of the drug as well as the most important amino acids in the interaction of bioactive compounds with their respective enzymes. The results of energy calculations obtained by DFT, in the MFCC approach, showed that to the system INADH-inhA, the most important residue for the affinity ligand with the site of the inhA was the K165, with the attractive energy -101.97 kcal/mol, while to the system (4R-INADP)- frA, the amino acid with the most attractive interaction was the R44, having na energy of interaction around -272.64 kcal/mol. The regions that showed the highest affinity ligands with their target enzymes, in both cases it was found that the region related to the cofactors NADH (of INADH) and NADP (of 4R-INADP) showed the most energetic interactions with the active site residues of proteins, mainly the hosphoric groups.