Inhibiting the oligomerization of mycobacterial DNA-directed RNA polymerase (RNAP) using natural compound via in-silico techniques

Mycobacterium tuberculosis (Mtb) is responsible for the spread of tuberculosis (TB). The current study employed virtual screening of 2569 natural compounds against the DNA-directed RNA polymerase (RNAP) of Mtb to identify the possible binders that can inhibit its function. The in-silico methodology included molecular docking to the compounds, further, the stability and flexibility of the best complexes were studied using molecular dynamics simulation, the MM/GBSA binding free energy technique with energy decomposition, PCA, FEL, steered MD simulation, and umbrella sampling. Individual virtual screenings were conducted for the five RNAP subunits (chains A, B, C, D, and E) to identify a compound capable of inhibiting RNAP oligomerization. A promising compound, isoestradiol 3-benzoate, exhibited a low binding score (−7.28 ​kcal/mol to −8.21 ​kcal/mol) and showed binding ability with all subunits of the protein. Thus, the five complexes with isoestradiol 3-benzoate were selected for molecular dynamics simulation analysis. Furthermore, RMSD showed that isoestradiol 3-benzoate bound with chain E showed the lowest RMSD of 0.49 ​nm, while with chains A and B it had the most stable and consistent conformations with RMSD of 1.75 ​nm and 1.2 ​nm, respectively. The H-bond between isoestradiol 3-benzoate and chains C and E showed the highest occupancy (58.27 ​%, 45.33 ​%, and 50.80 ​%, 42.25 ​%, 11.75 ​%). Moreover, the MMPBSA technique showed that isoestradiol 3-benzoate had a strong association with chains B and C (ΔGbind ​= ​−126.25 ​± ​2.03 and −129.27 ​± ​2.25). Additionally, free energy decomposition, PCA, FEL-steered MD simulation, and umbrella sampling were also performed to validate the association of the ligand with the protein. Isoestradiol 3-benzoate binds strongly to chains B and E; therefore, it should be considered as viable candidate for inhibiting the formation of RNAP protein complex, concluded in this study.