For VS, scientists have various commercial, public or in-house databases at their disposal. Many groups have concentrated on modifying the previously identified small-molecule compounds or mimicking the native ligands within known binding sites. Nevertheless, there are also examples revealing novel chemical classes of potential modulators. Studies conducted so far are still mainly focused on targeting the LRR domain of TLRs. There has been no noticeable progress in the design of modulators for the TIR domain. Many recent studies have been carried out on TLR2. For instance, Murgueitio et al. used a shape-and feature-based similarity VS to screen some commercially available databases. For similarity search, they used the previously discovered TLR modulators from Guan et al. and Liang et al. . The authors tested selected hits and four (AG1-AG4) were found to synergistically increase the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) B) activation induced by the known lipopeptide ligand Pam3CSK4. Further studies indicated that the tested compounds could act as ago-allosteric modulators of TLR2.