Desidroquinato desidratase II como alvo para o planejamento racional de fármacos contra o Mycobacterium tuberculosis e Helicobacter pylori

Abstract

Infections caused by pathogenic microorganisms such as Mycobacterium tuberculosis and Helicobacter pylori have shown alarming rates regarding its incidence and prevalence in Brazil. Therefore, there is an urgent need to design new, safe and efficient drugs to hostile these infections. Drug structure-based drug planning is a technology that can be employed in this process, with only the knowledge of a target of interest for disease and ligands with varying affinities. Dehydroquinate dehydratase II (DHQase II) is an enzyme that is part of the biosynthetic pathway of these bacteria, called the shikimate pathway. This pathway is considered of paramount importance for the growth of these pathogenic microorganisms. Given this, DHQase II has become an attractive target for rational planning of new inhibitors. The general objective of this work was the rational design of new active compounds that may inhibit this enzyme. The use of linear regression techniques to develop predictive QSAR models (2D, 3D, 4D and Hybrid) with excellent statistical parameters, made possible the elaboration of unpublished molecules without the real need to perform biological activity test in vitro or in vivo. The descriptors of the respective linear models linked to the Activity Cliffs analysis corroborated the elucidation of the intermolecular interactions of the inhibitors with the DHQase II receptor site of the two bacteria. The data obtained serve as a guide for the rational planning of new potent and highly selective antibiotics to act in the enzymatic inhibition of DHQase II.