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Previous issue date: 2013-01-28 === 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 ?. 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. === A Tuberculose continua sendo a causa mais comum de morte em decorr?ncia de um agente infeccioso. Entre os alvos identificados no genoma do Mycobaterium tuberculosis, enzimas da via do chiquimato merecem aten??o especial. A chiquimato quinase ? a quinta enzima da via do chiquimato, e tem sido identificada em fungos, organismos do filo apicomplexa, plantas e procariontes. Esta via metab?lica ? composta por sete passos, que catalisam sequencialmente a convers?o de eritrose-4-fosfato e fosfoenolpiruvato em corismato; e ? respons?vel pela bioss?ntese de amino?cidos arom?ticos. Chiquimato quinase parece ser essencial para a sobreviv?ncia do Mycobacterium tuberculosis, uma vez que ? ausente no homem, esta enzima ? considerada como um alvo para o desenvolvimento de quimioter?picos e medicamentos contra a tuberculose. O objetivo ? identificar poss?veis inibidores, focando as simula??es de docking molecular no s?tio de liga??o do ATP da enzima. O programa usado nas simula??es foi o Molegro Virtual Docker e a intera??o prote?na-ligante foi testada em 12 estruturas cristalogr?ficas e logo ap?s, escolhido um protocolo de docking a partir de valores de RMSD abaixo de 2?. O m?todo foi validado usando o melhor protocolo de re-docking no Virtual Screening atrav?s do Fator de Enriquecimento que obteve resultado de 24,57%, que ? considerado adequado para as simula??es de docking molecular focados em quinases. O presente protocolo de docking foi aplicado em um banco de dados com mais de 80.000 mol?culas. A an?lise dos resultados identificaram 5 potenciais inibidores da chiquimato quinase. Na an?lise das intera??es intermoleculares entre a enzima e os ligantes foram identificadas caracter?sticas estruturais respons?veis pela afinidade da liga??o pelo ligante. Este ? o primeiro estudo de docking molecular focado no bols?o de liga??o do ATP da chiquimato quinase.
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