Design of new drugs against tuberculosis; developing inhibitors for phosphodiesterase

Tuberculosis is a bacterial and infectious disease. Mycobacterium tuberculosis microbe is the cause of this disease. New antituberculosis drugs are needed constantly while most of the bacteria are resistant to antibiotics nowadays. Therefore, instead of existing medicines, choosing mechanisms including adaptation, growth and survival of bacteria to the environment is a new drug target. Many bacteria use signal transmission to response external conditions for adaptation and grow. Most bacteria have this communication using secondary messenger signal transmission. Approaches targeting biologically active substances involved in this transmission are a good drug target. In this study, we investigated the identification of new anti-tuberculosis drugs targeting the phosphodiesterase (PDE) enzyme included in the secondary messenger process, which catalyses the opening reaction of cyclic dinucleotide monophosphate (c-di-AMP) by computer approach (Docking). A total of 59 ligands were docked to PDE whose x-ray structure was obtained from the potein data bank (5ceu), which also inolves the open form of c-di-AMP. A large number of ligands are already used as the inhibitors of human PDEs and some in the trearment of tuberculosis while some are from natural sources, mainly from Curcuma longa L. When the dock score of the original ligand was determined that the orignal ligand was docked to the protein with a dock score of -82.02 kcal mol-1, the dock scores of 16 of the ligands was between -40 and -50 kcal mol-1 and two of them were below -50. The present results provide a detailed binding mode of ligands with Mtb PDE which could be used as a stand to develop new drugs against tuberculosis