The systematic modeling studies and free energy calculations of the phenazine compounds as anti-tuberculosis agents

Phenazine compounds have good activity against Mycobacterium tuberculosis (MTB). Based on the reported activities that were obtained in MTB H37Rv, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was built to design novel compounds against MTB. A fivefold cross-validation method and external validation were used to analyze the accuracy of forecasting. The model has a cross-validation coefficient q²=0.7 and a non-cross-validation coefficient r² = 0.903, indicating that the model has good predictive possibility. The design of anti-pneumococcus MTB compounds was guided by the obtained 3D-QSAR model, and several compounds with better activity were obtained. To test the activity of these compounds, molecular docking, molecular dynamics simulation, and post-simulation analysis of the already reported drug targets in MTB were carried out. Among the total 15 drug targets, only three targets (Rv2361c, Rv2965c, and Rv3048c) were selected based on the docking results. Initial results reported that these compounds possessed good inhibition activity for Rv2361c. The top nine complexes of Rv2361 ligands were only subjected to MD simulation which resulted in a stable dynamics of the structures and showed a residual fluctuation in inhibitors binding pocket. Free energy reported that overall, the derivatives hold strong energy against the protein target. Energetic contribution results showed that residues, Asp76, Arg80, Asn124, Arg127, Arg244, and Arg250, play a major role in total energy. Systems biology approach validates shortlisted drug effect on the entire system which might be useful to predict potential drug in wet lab as well. Communicated by Ramaswamy H. Sarma.