Natural products from Brazilian biodiversity identified as potential inhibitors of PknA and PknB of M. tuberculosis using molecular modeling tools.

Mycobacterium tuberculosis was discovered in 1882 by Robert Koch but, since its discovery, the tuberculosis (TB) epidemic has endured, being one of the top 10 causes of death worldwide. Drug-resistant TB continues to be a public health threat and bioactive compounds with a new mode of action (MoA) are needed to overcome this. Since natural products are described as important sources for the development of new drugs, the objective of this work was to identify potential ligands from Brazilian natural products (NPs) for M. tuberculosis targets using molecular modeling tools. Using chemogenomics we identified the Serine/Threonine Protein Kinase PknB as a putative target for 13 NPs from a database from Brazilian biodiversity (NuBBE). Literature data supported further investigation of NuBBE105, NuBBE598, NuBBE936, NuBBE964, NuBBE1045, and NuBBE1180 by molecular docking and dynamics. Key interactions were observed with PknB and simulations confirmed stability and favorable binding energies. Considering structural similarity with PknB, we further explored binding of the NPs to PknA, critical for M. tuberculosis survival, and all of them resembled important interactions with the enzyme, showing stable and favorable binding energies, whilst van der Waals interactions seem to play a key role for binding to PknA and PknB. NuBBE936 and NuBBE1180 have already had their antimycobacterial activity reported and our results can provide a basis for their MoA. Finally, the other NPs which have not been tested against M. tuberculosis deserve further investigation, aiming at the discovery of antimycobacterial drug candidates with innovative MoA.