Simulação computacional do sistema proteína-ligante : estudo da chiquimato quinase de Mycobacterium tuberculosis

Abstract

Tuberculosis remains the most common cause of death due to an infectious agent. Among targets identified in Mycobaterium tuberculosis genome, enzymes of the shikimate pathway deserve special attention. Shikimate kinase is the fifth enzyme of the shikimate pathway, which has been identified in fungi, apicomplexans, plants and prokaryotes. This metabolic route is composed of seven steps, which converts erythrose-4-phosphate and phosphoenol pyruvate to chorismic acid and is responsible for the biosynthesis of aromatic amino acids. Shikimate kinase has been shown to be essential to the survival of Mycobacterium tuberculosis, and since it is absent in human, this enzyme is considered to be a target for chemotherapeutic for development of antitubercular drugs. The aim here is to identify possible inhibitors, focusing on simulations of molecular docking in the ATP-binding site of the enzyme. The program used in the simulations was the Molegro Virtual Docker and protein-ligand interactions were tested in 12 crystallographic structures and then, it was choosen a protocol which generated docking RMSD values below 2 Å. Application of this docking protocol to a decoy dataset generated a enrichment factor of 24.57, which is considered adequate for molecular docking simulations focused on kinases. The present docking protocol was then applied to a small-molecule database with over 80,000 entries. Analysis of the results identified 5 potencial shikimate kinase inhibitors. Examination of the intermolecular interaction between enzyme and the ligands identified the main structural features responsible for ligand-binding affinity. This is the first molecular docking study focused on the ATP-binding pocket of shikimate kinase.