Molecular modelling and activity analysis of mycobacterium tuberculosis DNA gyrase B ATPase active site

Abstract

Computer-based algorithms and statistical techniques such as receiver operating characteristic (ROC) curves are increasingly used for the design of new ligands. X-ray crystallographic data and homology models allow examining the interactions between ligands and biomacromolecules using different algorithms and techniques. DNA gyrase enzyme inhibition is an alternative approach to clinical antimicrobial therapy for multi-drug resistant Mycobacterium tuberculosis (MT). In this study, different datasets were created by enriching 1,442,716 compounds using known DNA GyrB ATPase inhibiting molecules. HTVS was performed on a previously designed homology model of MT DNA GyrB ATPase active site and true-positive scores were verified using ROC curves. Furthermore, 11 molecules with high scores were tested for their activity and the compound with the 5-(4-aminophenoxy)-2-(3-aminophenyl)-2,3-dihydro-1H-isoindole-1,3-dione structure was found to have similar activities to standard novobiocin. Finally, molecular interaction field and distance/interaction probability analyses were performed on the pose to identify new probable active derivatives of this compound.