Exploring Natural Compounds as Inhibitors Against DNA-directed RNA Polymerase in Possible Allosteric Sites Employing in silico Strategies

According to the World Health Organization, tuberculosis is the deadliest disease caused by a single bacterial pathogen. Tuberculosis is caused by the Gram-positive bacillus Mycobacterium tuberculosis, and its typical treatment regimen consists of four drugs; one of them is rifampicin, which targets the β-subunit of DNA-directed RNA polymerase. Because of the growing resistance to this drug, it is essential to develop new antibiotics that can inhibit the rifampicin-resistant strain. Through a systematic strategy applying computational methods, it is possible to explore the inhibition sites of a receptor and determine the affinity of certain compounds towards these sites. In this work, a global exploration of a series of natural compounds was realized against RNA polymerase by doing molecular docking calculations. These compounds, according to the literature, have anti-mycobacterial action or act against the β-subunit of RNA polymerase. The affinity energy analysis showed favorable affinity energies for the natural compounds, comparable to the reference drug and interactions with amino acids at the active site and allosteric sites. Based on this analysis, it confirms the possibility of an alternative site to the active site that would allow binding and inhibiting this protein by simultaneously targeting them, which it would potentially enable an additive or synergistic effect, because both the active and the possible allosteric sites would be inhibited. These findings contribute to the knowledge of this receptor and the possible and alternative action modes of compounds against the protein.