Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8

• Published in: PloS one 2017-06, Vol.12 (6), p.e0178846
• Main Authors: Kubli-Garfias, Carlos, Vázquez-Ramírez, Ricardo, Trejo-Muñoz, Cynthia, Berber, Arturo
• Format: Article
• Language: English
• Subjects: Adjuvants; Adjuvants, Immunologic - chemistry; Amino Acid Motifs; Antifungal agents; Antineoplastic drugs; Atomic structure; Binding Sites; Biological response modifiers; Biology and Life Sciences; Chemical bonds; Chemistry; Computational chemistry; Computer applications; Correlation; Crystals; Cytokines; Design; Design analysis; Design engineering; Design improvements; Drugs; Electrostatic properties; Free energy; Humans; Hydrogen; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Imidazole; Imidazoles - chemistry; Immune response; Immune system; Immunologic adjuvants; Immunostimulants; Immunosuppressive agents; Interferon; Interferon regulatory factor; Kinetics; Ligands; Mathematical analysis; Medicine and Health Sciences; Models, Molecular; Molecular structure; NF-κB protein; Pharmacology; Physical Sciences; Physicochemical analysis; Physicochemical properties; Polar environments; Polar regions; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Proteins; Quantitative Structure-Activity Relationship; Quantum mechanics; Quinolines - chemistry; Receptor mechanisms; Solvation; Static Electricity; Thermodynamics; TLR7 protein; Toll-Like Receptor 8 - agonists; Toll-Like Receptor 8 - chemistry; Toll-Like Receptor 8 - immunology; Toll-like receptors; Toxicity; Viral infections
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178846

Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll-like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-κB (IRF-NFκB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity.