Possible allosteric binding site on Gyrase B, a key target for novel anti-TB drugs: homology modelling and binding site identification using molecular dynamics simulation and binding free energy calculations

Although tuberculosis (TB) is a treatable disease, it still impacts highly on the morbidity and mortality of people in sub-Saharan Africa. This is largely attributed to drug resistance to the currently available drugs as well as co-infection with HIV. The emergence of multidrug-resistant and extensively drug-resistant TB has necessitated the urgent need for the development of new drugs. DNA Gyrase B, a previously validated target for the aminocoumarins poses an attractive enzyme to target for the development of novel potent drugs. Previous biochemical assays suggest that the inhibitor diospyrin, binds to a novel binding site, close to the ATP binding site of the N-terminal domain of Gyrase B. To date, however, no available crystal structure of diospyrin in complex with Gyrase B has been reported. Thus, to investigate the position of this potential binding site, a robust homology model was built and validated, followed by docking and MD simulations. Thermodynamic calculations were used to estimate binding affinity. Binding free energy calculations revealed subtle differences in the binding at each site, however, the comprehensive computational analyses presented here, provide a substantially extensive illustration of the binding themes and affinities for each site, which offer value for the further design of novel inhibitors.