In Figure we presented examples of scaffolds of both agonists and antagonists targeting the LRR domain of TLRs proposed in reviewed publications. Also, we showed the localisation of the designed small-molecule modulators in relation to the subunits of the TLRs. In Supplementary Table we gathered the structures of all the best hits from the reviewed research papers. As can be seen from the above-mentioned studies, many groups used the information from the previously designed modulators either for introducing some modifications aimed at increasing their activity or for obtaining models for VS and further studies. In the reviewed papers we encountered both the strategy to design modulators structurally similar to known ligands and compounds with a completely different structure. Interestingly, the targeting sites remain the same, which highlights the challenges in reconstruction of TLRs structure and difficulties with the identification of other potential binding sites which could affect TLRs function. We could also notice that some of the proposed modulators were able to influence the signalling pathways in various TLRs. Nevertheless, the molecular basis of their selectivity have not been thoroughly