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.

结核分枝杆菌于 1882 年由罗伯特·科赫发现，但自发现以来，结核病 (TB) 流行一直持续，成为全球十大死因之一。耐药结核病仍然是公共卫生威胁，需要具有新作用模式 (MoA) 的生物活性化合物来克服这一问题。由于天然产物被描述为新药开发的重要来源，因此这项工作的目的是从巴西天然产物 (NPs) 中鉴定结核分枝杆菌的潜在配体使用分子建模工具的目标。使用化学基因组学，我们将丝氨酸/苏氨酸蛋白激酶 PknB 鉴定为来自巴西生物多样性 (NuBBE) 数据库的 13 个 NPs 的推定靶标。文献数据支持通过分子对接和动力学进一步研究 NuBBE105、NuBBE598、NuBBE936、NuBBE964、NuBBE1045 和 NuBBE1180。用 PknB 观察到关键的相互作用，并且模拟证实了稳定性和有利的结合能。考虑到与 PknB 的结构相似性，我们进一步探索了 NP 与 PknA 的结合，这对结核分枝杆菌至关重要生存，并且它们都类似于与酶的重要相互作用，显示出稳定和有利的结合能，而范德华相互作用似乎在与 PknA 和 PknB 结合方面起关键作用。NuBBE936 和 NuBBE1180 已经报告了它们的抗分枝杆菌活性，我们的结果可以为它们的 MoA 提供基础。最后，其他尚未针对M. tuberculosis进行测试的 NP值得进一步研究，旨在发现具有创新 MoA 的抗分枝杆菌候选药物。