Target fishing and molecular modeling of nitroheteroaylchalcones with potent antituberculosis activity

Abstract

Computer-aided drug planning strategies have contributed to the research and development of new anti-tuberculosis (TB) drugs to avoid resistance and reduce treatment time and the number of drugs used in therapy. The aim of work was to carry out a docking study to identify the possible mechanism of action of the hits LabMol73, 84, 86 and 93 previously tested in the Microplate Assay Blue Alamar (MABA), Low Oxygen Recovery Assay (LORA) assays in sensitive strains from M.tb. H37Rv and resistant to the standard drugs rifampicin and isoniazid, due to the promising inhibitory result against these strains, suggesting a different mechanism of action from existing drugs. The reverse virtual screening was performed on the Pharmmapper platform, which identifies targets by pharmacophoric model. The most promising targets have been validated. The DM was performed in the OpenEye Maestro program for analysis of poses and energy score. Sixteen targets M.tb. H37Rv were identified and only nine demonstrated viability for computational testing. The most promising results were observed in the mycolic acid cyclopropane synthase (PDB:1L1E) and pantothenate synthetase (PDB:1N2B) targets. Since, in the target 1L1E score results obtained were between -6.998 to -7.767 kcal/mol. In the 1N2B target the results were between -6.421 to -7.293 kcal/mol, presenting themselves as the most promising targets due to their similar score scores between the two targets suggesting that the mechanism of action may be the inhibition of one of these targets. These targets proved to be promising for elucidating the mechanism of action of the analyzed nitro heteroaryl chalcones, as they corroborate the assay against resistant strains, demonstrating that standard drugs have activity against other targets and also because mycolic acid and pantothenate are directly linked to virulence and resistance of M.tb. H37Rv.