Toll-like receptor 7 (TLR7) is activated in response to the binding of single-stranded RNA. Its over-activation has been implicated in several autoimmune disorders, and thus, it is an established therapeutic target in such circumstances. TLR7 small-molecule antagonists are not yet available for therapeutic use. We conducted a ligand-based drug design of new TLR7 antagonists through a concerted effort encompassing 2D-QSAR, 3D-QSAR, and pharmacophore modelling of 54 reported TLR7 antagonists. The developed 2D-QSAR model depicted an excellent correlation coefficient (R2training: 0.86 and R2test: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R2training: 0.95 and R2test: 0.84) demonstrated a significant contribution of electrostatic potential and steric fields towards the TLR7 antagonism. This consolidated approach, along with a pharmacophore model with high correlation (Rtraining: 0.94 and Rtest: 0.92), was used to design quinazoline-core-based hTLR7 antagonists. Subsequently, the newly designed molecules were subjected to molecular docking onto the previously proposed binding model and a molecular dynamics study for a better understanding of their binding pattern. The toxicity profiles and drug-likeness characteristics of the designed compounds were evaluated with in silico ADMET predictions. This ligand-based study contributes towards a better understanding of lead optimization and the future development of potent TLR7 antagonists.

Undesirable activation of endosomal toll-like receptors TLR7 and TLR9 present in specific immune cells in response to host-derived ligands is implicated in several autoimmune diseases and other contexts of autoreactive inflammation, making them important therapeutic targets. We report a drug development strategy identifying a new chemotype for incorporating relevant structural subunits into the basic imidazopyridine core deemed necessary for potent TLR7 and TLR9 dual antagonism. We established minimal pharmacophoric features in the core followed by hit-to-lead optimization, guided by in vitro and in vivo biological assays and ADME. A ligand–receptor binding hypothesis was proposed, and selectivity studies against TLR8 were performed. Oral absorption and efficacy of lead candidate 42 were established through favorable in vitro pharmacokinetics and in vivo pharmacodynamic studies, with IC50 values of 0.04 and 0.47 μM against TLR9 and TLR7, respectively. The study establishes imidazopyridine as a viable chemotype to therapeutically target TLR9 and TLR7 in relevant clinical contexts.

No abstract

hERG is considered to be a primary anti-target in the drug development process, as the K + channel encoded by hERG plays an important role in cardiac re-polarization. It is desirable to address the hERG safety liability during early-stage development to avoid the expenses of validating leads that will eventually fail at a later stage. We have previously reported the development of highly potent quinazoline-based TLR7 and TLR9 antagonists for possible application against autoimmune disease. Initial experimental hERG assessment showed that most of the lead TLR7 and TLR9 antagonists suffer from hERG liability rendering them ineffective for further development. The present study herein describes a coordinated strategy to integrate the understanding from structure-based proteinligand interaction to develop non-hERG binders with IC 50 > 30 μM with retention of TLR7/9 antagonism through a single point change in the scaffold. This structure-guided strategy can serve as a prototype for abolishing hERG liability during lead optimization.