Drug resistant tuberculosis has threatened all the advances that have been made in TB control at the global stage in the last few decades.
DNA gyrase enzymes are an excellent target for antibacterial
drug discovery as they are involved in essential functions like DNA replication. Here we report, a successful application of high throughput virtual screening (HTVS) to identify an inhibitor of Mycobacterium
DNA gyrase targeting the wild type and the most prevalent three double mutants of
quinolone resistant
DNA gyrase namely A90V+D94G, A74S+D94G and A90V+S91P. HTVS of 179.299 compounds gave five compounds with significant binding affinity. Extra presicion (XP) docking and MD simulations gave a clear view of their interaction pattern. Among them,
chebulinic acid (CA), a phytocompound obtained from Terminalia chebula was the most potent inhibitor with significantly high XP docking score, -14.63, -16.46, -15.94 and -15.11 against wild type and three variants respectively. Simulation studies for a period of 16 ns indicated stable
DNA gyrA-CA complex formation. This stable binding would result in inhibition of the
enzyme by two mechanisms. Firstly, binding of CA causes displacement of catalytic Tyr129 away from its target
DNA-
phosphate molecule from 1.6 Å to 3.8-7.3 Å and secondly, by causing steric hindrance to the binding of
DNA strand at
DNA binding site of
enzyme. The combined effect would result in loss of cleavage and religation activity of
enzyme leading to bactericidal effect on
tuberculosis. This phytocompound displays desirable quality for carrying forward as a lead compound for
anti-tuberculosis drug development. The results presented here are solely based on computations and need to be validated experimentally in order to assert the proposed mechanism of action.