The authors successfully designed mimetics through docking with MD2 and confirmed the stability of the modulators by performing MD simulations. Subsequently, compounds were synthesised and tested to confirm their ability to bind to MD2 and inhibit LPS-stimulated TLR4 activation. In a very recent study, Pérez-Regidor et al. focused on a different strategy of finding non-LPS-like modulators among the approved drugs and drug-like molecules from commercial, public, and in-house libraries of compounds. Based on the structure-and ligand-based VS, combined with docking and biological results, the authors presented a common scaffold consisting of two hydrophobic moieties separated by a polar linker. They showed that one large hydrophobic moiety occupies the hydrophobic MD2 cavity, while the second moiety is associated with the same hydrophobic region as one of the lipid A alkyl chains, and the polar linker occupies the entrance to the pocket.