Subtle differences in chemical pattern between human toll‐like receptor 8 agonists and antagonists: Emerging chemical patterns analysis

Abstract

Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8. K E Y W O R D Sagonist, antagonist, emerging chemical pattern, prediction, toll-like receptor 8

Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein–Protein Interface

“…Furthermore, our experimental results were in good agreement with Lu lab. 29 Interestingly, superimposition of the structure of TLR8 derived from the TLR8/TH1027 complex onto the unliganded TLR8 produced a root mean square deviation (rmsd) value of 2.2 Å. By comparison, its superimposition with the agonist-bound, active form of TLR8 produced an rmsd value of 7.5 Å, indicating that the conformation of TLR8/TH1027 complex was closer to the resting state.…”

“…With 3-pyridyl- ( 3n ) and cyclohexyl- ( 3o ) substitutions at the R 3 position, the inhibitory activities of TH1027 totally disappeared, indicating that the π–π interaction is vital for the activities. Furthermore, our experimental results were in good agreement with Lu lab . Interestingly, superimposition of the structure of TLR8 derived from the TLR8/ TH1027 complex onto the unliganded TLR8 produced a root mean square deviation (rmsd) value of 2.2 Å.…”