3D QSAR, Docking, Molecular dynamics simulations and MM-GBSA studies of Extended Side Chain of the Antitubercular Drug (6S) 2-Nitro-6-{[4-(trifluoromethoxy) benzyl] oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine.

PA-824 analogues have been proposed on a promising approach for treating MDR/XDR tuberculosis. In order to understand the structural requirement of reported extended side chain analogues were studied to get insight into their structural requirements responsible for high affinity as a ligand-based pharmacophore, 3D-QSAR model have been developed. A structurally diverse set of 84 molecules was divided into 17 molecules of test set and rest of the 67 molecules of training set. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R2 = 0.8988 for training set compounds, higher variance ratio F= 127.3 and the model generated showed excellent predictive power, with a correlation coefficient of structure to analyses Q2= 0.8543 for a randomly chosen test set of 17 compounds. Docking and molecular dynamics studies revealed the better binding interaction of inhibitor binding pocket of deazaflavin dependent nitroreductase (Ddn) with cofactor F420 crystal. The docking studies were also carried out wherein the active and inactive molecules were docked into inhibitor binding pocket of deazaflavin dependent nitroreductase (Ddn) with cofactor F420crystal the enzyme inhibition interaction. The MM-GBSA binding free energy calculations confirmed that natural ligand has a decrease of 36.212 kcal/mol in the free energy of binding compared to the strongest binding compound (molecule 63). Statistical results of the generated model are significant which recommends that this model may be acceptable for designing of various novel derivatives in future.