Listeriolysin inhibition and drug design

Listeriolysine-O (LLO) is the responsible of Listeria monocytogenes pathogenicity and the risk of disease might boost when the suppressed immune host or pregnant women has been exposed to this bacterial toxin. According to the crystal structure of LLO, it consists of four distinct domains, which have been called D1 to D4 and each of them, playing a different role in LLO functionally. This study was conducted to intend to illustrate some sequences of LLO which are more conserved in D1 to D4. Describing these sequences can be of a great importance for modeling an inhibitor for inhibiting oligomerization of LLO monomers. LLO is pore forming toxin (PFTs) and its monomers oligomerize into ring of 50 monomers. Accordingly this virtual experiment is conducted to aim for modeling an essential inhibitor for prohibiting oligomerization of LLO monomers, which causes to induce inhibiting of oligomer formation and prevent pore forming of LLO. To do this, we selected a library containing 200.000 drug likes against the oligomerizing centers. Top 5 successive hits were then selected for supplementary pharmacological analysis. The first successive hit ([C@H]([C@@H]([C@H](CCCCCCCCCCCCCC)O)O)(C)CO) was then selected for further refinement steps and after removing a propane group and changing five single bonds into double the rotatable bonds were managed to fit its pharmacophore model more specific for LLo. The final modified structure ((1E)-1-[(E)-(E)-4-(3-Cyclopenten-1-yl)-6,7,9-trihydroxy-8-methylene-2-nonenylideneamino]-1,4-pentadien-3-one) also was checked for toxicity and unspecific target binding. The PROTOX results indicated that there is not any toxicity target for RD-1 ligand.