Small-Molecule TLR8 Antagonists via Structure-Based Rational Design.

ABSTRACT: Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC₅₀ values. Two X-ray crystallographic structures validated th

SUBMITTER: Hu Z 

PROVIDER: S-EPMC6195466 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature