title: Design of anti-BVDV drug based on common chemical features, their interaction, and scaffolds of TLR8 agonists.
abstract: In the absence of an experimental bTLR8 structure, recent studies have called attention to the fact that bTLR8 can also be activated by hTLR7/hTLR8 agonist, such as antiviral imidazoquinoline derivatives of resiquimod (R848) and imiquimod (R837) as well as some guanine nucleotide analogs with a scaffold structure related to the nucleic acids of ssRNA virus. In particular, the known small agonists (namely CL075, CL097 and R848) have been targeted to determine distinguishable deciding factors in complex with dimeric bTLR8-ECDs in comparison to ligand-induced activated hTLR8-ECDs. According to basic knowledge, the deciding eligibility criteria can be subsequently applied in our bTLR8 model to characterize the 3D-arrangement of chemical features (pharmacophore) and to investigate the distinct restrictions affecting species-specificity on dual TLR7/TLR8 small agonists suggested in previous works. Despite the lack of extensive structural biology studies regarding the interaction of bTLR8-ECDs with the agonists, our complex models of bTLR8-ECDs and the known agonists were applied to identify the deciding factors required for the interactions from agonist-based and (bTLR8-agonist complexes) structure-based pharmacophores. These pharmacophore constraints impose their essential chemical features to active bTLR8 receptors. The characterized pharmacophores all were employed in the virtual screening of candidates with a further acting factor of calf immune enhancer. Two hits were suggested as satisfying all decision factors to identify a potent bTLR8-specific agent with novel scaffolds dissimilar to imidazoquinoline analogues lacking overall homogeneity.
authors: Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea. Electronic address: hanha@korea.kr.
authors: Han-Ha
authors: HH
authors: Chai
authors: Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea.
authors: Dajeong
authors: D
authors: Lim
authors: BIOVIA Korea, C-602 Korea Bio Park, 700, Daewangpangyo-ro, Bundang-Gu, Seongnam-Shi, Gyeonggi-Do, 463-400, Republic of Korea.
authors: Jae Eun
authors: JE
authors: Suk
authors: Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea.
authors: Bong-Hwan
authors: BH
authors: Choi
authors: Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea.
authors: Yong-Min
authors: YM
authors: Cho
mesh_terms: D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D002417:Cattle; D030241:Diarrhea Virus 1, Bovine Viral / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D000077271:Imiquimod; D062105:Molecular Docking Simulation; D010802:Phylogeny; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011804:Quinolines / Q000737:chemistry*; D016415:Sequence Alignment; D013045:Species Specificity; D040681:Structural Homology, Protein; D013844:Thiazoles / Q000737:chemistry*; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000737:chemistry / Q000145:classification / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; C551788:CL 075; C547051:CL097 compound; D007093:Imidazoles; D011804:Quinolines; D013844:Thiazoles; D051200:Toll-Like Receptor 8; D017361:Viral Nonstructural Proteins; D000077271:Imiquimod; C402365:resiquimod
keywords: Bovine Toll-like receptor 8 (bTLR8); Bovine viral diarrhea virus (BVDV); Ectodomain (ECD); Ligand-recognition domain; Pharmacophore modeling; Small agonists