Identification of Lutzomyia longipalpis Odorant Binding Protein Modulators by Comparative Modeling, Hierarchical Virtual Screening, and Molecular Dynamics

Visceral leishmaniasis (VL) is the second most important vector-borne disease in the world. It is transmitted by Lutzomyia longipalpis in America; therefore, controlling the vector is essential to prevent the disease, especially using traps with chemical attractants. It is known that odorant binding proteins (OBPs) act at the first odor selection level, so in silico methodology was used to identify putative vector chemical modulators based on OBPs on known ligand structures. Therefore, 3D structures of L. longipalpis OBP were predicted through different comparative modeling methods. The best model was subjected to molecular dynamics studies. Then, a hierarchical virtual screening approach filtered OBP modulator-like compounds from ZINC12 biogenic database based in global chemical space, using principal components from ChemGPS-NP server. Such compounds then were evaluated and ranked according to their affinity with the OBP orthosteric site by molecular docking in DOCK 6.7. The compounds were scored by Grid Score function and top five ranked poses had their intermolecular complex interactions analyzed in PLIP server. Most ligands in the top of the rank were lysophospholipids, which could potentially interact with the OBP hydrophobic pocket through Phe72, Tyr76, Ile79, Ala87, Lys88, Asp92, Phe61, Leu75, Trp113, His120, and Phe122 residues and H-bonding with His120 and Phe122. Next, compounds in the top of the rank were evaluated by 50 ns MD and the results showed that the phosphate group of these compounds could set a salt bridge with His110. Additionally, Tyr76, Ala87, Met91, Trp113, and Phe122 were important to hydrophobic interactions with the ligand. These results highlight the importance of accurate assessments such as MD studies in order to analyze the docking results in the identification of new odorant modulators.