Bioquímica quântica da interação ligante-alvo no combate ao mycobacterium tuberculosis multirresistente

Abstract

Tuberculosis is a worldwide health problem caused by Mycobacterium tuberculosis and aggravated by the resistance mechanisms developed by this bacterium against the drugs used in its treatment. Thus, the development of drugs capable of eliminating multidrug-resistant strains, characterized by those that have resistance to the most important drugs - rifampicin and isoniazid - becomes crucial. Thereby, this work aims to perform a structural and energetic study of the kanglemycin and rifampicin interactions in complex with RNA Polymerase; also BDM72201, BDM72719, BDM76060 and BDM76150 with the transcriptional repressor EthR2, as a way to boost the action of ethionamide. Using crystallographic data from these systems, calculations of the interactions of each ligand with their respective receptors were performed within the density functional theory (DFT), and the binding energy of each molecule with the amino acid constituents of the binding site was obtained by applying the molecular fractionation with conjugate caps (MFCC). Thus, results showed that kanglemycin is able to bind to RNA polymerase in the same way as rifampicin, having -63.61 Kcal/mol and -65.68 Kcal/mol total energy, respectively, and sharing 79 residues at the binding site. In the presence of the S447L mutation, often associated with rifampicin resistance, kanglemycin maintains its strong interaction with its target, generating an overall energy of -64.00 Kcal/mol. BDM72201, BDM72719, BDM76060 and BDM76150 components share 68 residues of the same binding site. BDM72201 and BDM72719 attach to the site in a weaker way, showing energies of -19.56 Kcal/mol and -21.56 Kcal/mol, respectively; whereas BDM76060 (- 65.88 Kcal/mol) and BDM76150 (-66.13 Kcal/mol) produce stronger binding and have greater potential to act as EthR2 inhibitors. Therefore, it was evidenced that kanglemycin has great potential to be inserted into clinical practice as a rifampicin substitute and the BDM76150 as an ethionamide booster.