Microbial-based natural products as potential inhibitors targeting DNA gyrase B of Mycobacterium tuberculosis: an in silico study

Introduction: Since the emergence of Mycobacterium tuberculosis (MBT) strains
resistant to most currently used anti-tubercular drugs, there has been an urgent
need to develop efficient drugs capable of modulating new therapeutic targets.
Mycobacterial DNA gyrase is an enzyme that plays a crucial role in the replication
and transcription of DNA in MBT. Consequently, targeting this enzyme is of
particular interest in developing new drugs for the treatment of drug-resistant
tuberculosis, including multidrug-resistant tuberculosis (MDR-TB) and
extensively drug-resistant tuberculosis (XDR-TB).
Methods: In the present study, multiple computational tools were adopted to
screen a microbial-based natural products database (NPAtlas) for potential
inhibitors of the ATPase activity of MBT DNA gyrase.
Results and discussion: Twelve hits were initially identified as the top candidates
based on their docking scores (ranging from −9.491 to −10.77 kcal/mol) and
binding free energies (−60.37 to −73.21 kcal/mol). Following this, computational
filters, including ADME-T profiling and pharmacophore modeling, were applied
to further refine the selection. As a result, three compounds 1-Hydroxy-D-788-7,
Erythrin, and Pyrindolol K2 emerged as the most promising, exhibiting favorable
drug-like properties. Notably, 1-Hydroxy-D-788-7, an anthracycline derivative,
demonstrated superior binding affinity in molecular dynamics simulations. The
RMSD values, ranging from 1.7 to 2.5 Å, alongside RMSF analysis and a detailed
evaluation of the established interaction forces, revealed that 1-Hydroxy-D-788-
7 was the strongest binder to Mycobacterial DNA Gyrase B. The stable binding and
favorable interaction profile highlighted 1-Hydroxy-D-788-7 as a top hit. These
comprehensive computational findings strongly support the potential of 1-
Hydroxy-D-788-7 as an effective anti-TB lead compound, warranting further
experimental validation to confirm its therapeutic efficacy.