title: Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds.
abstract: Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Euna
authors.initials: E
authors.lastname: Yoo
authors.forename: Deepak B
authors.initials: DB
authors.lastname: Salunke
authors.forename: Diptesh
authors.initials: D
authors.lastname: Sil
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Guo
authors.forename: Alex C D
authors.initials: AC
authors.lastname: Salyer
authors.forename: Alec R
authors.initials: AR
authors.lastname: Hermanson
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Ward H
authors.initials: WH
authors.lastname: Thompson
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanji
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000737:chemistry / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000737:chemistry / Q000502:physiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D006571:Heterocyclic Compounds; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8