Estudo bioquímico quântico de interações entre o receptor androgênico, RNAr e MCL-1 e Ligantes

Abstract

This thesis presents three researches carried out in the field of ab initio simulation, based on principles of Quantum Mechanics. The first study present the particularities of the interactions between the androgen receptor (AR) carrying a T877A mutation, which promotes promiscuity in the receptor, and two antagonist drugs cyproterone acetate and hydroxyflutamide (CPA and HFT) and an agonist compound (RLL). The interaction energies were obtained based on quantum chemistry methods based on Density Functional Theory (DFT) using the method Molecular Fragmentation with Conjugated Caps (MFCC). The results demonstrate the individual relevance between T877A-AR and the ligands, pointing out the main residues that make the interactions. The second study presents the analysis of the interaction between 16S ribosomal RNA and hygromycin B (hygB) is an aminoglycoside antibiotic that affects ribosomal translocation, using the MFCC strategy in light of the DFT and parameterization of dielectric constants. The results showed that nucleotides C1403, C1404, G1405, A1493, G1494, U1495, C1496 and U1498 had the most negative binding energies, making them strong candidates for stabilizing hygB in a suitable binding pouch of the 30S ribosomal subunit of prokaryotes. The third work presented here investigates the interactions between the anti-apoptotic protein MCL-1, which overexpression has the ability to block the apoptosis signaling pathway allowing for disordered cell growth, and seven chemical compounds with the potential to inhibit the protein . The methodology used here also uses quantum methods based on DFT, in addition to MFCC. The results showed that the residues Arg263, Met231, Val253 Phe270, Phe228, Phe254, Leu267 and Thr266 are of crucial importance for the binding of inhibitors to the hydrophobic pocket of MCL-1. The computational methods used in the three studies emerge as an elegant and efficient alternative for drug development.