Design, identification and validation of toll-like receptor 8 (TLR8) modulators using the Cu-CPT8m scaffold as a lead

Abstract

In the absence of pathogens Toll-like receptors become overactive, and a spontaneous inflammatory response is triggered leading to autoimmune disease. Thus, TLRs have been identified as potential drug targets and Cu-CPT8m and Cu-CPT9b were identified to mitigate the inflammatory response through antagonist activity at TLR8. The aim of this project was to model the critical pharmacophoric features of Cu-CPT8m and Cu-CPT9b into an average consensus pharmacophore to be used as a query for the identification of analogous structures using virtual screening. A virtual screening approach was adopted in the first phase of the study and a de novo design approach was adopted in the second phase of the study. In the virtual screening phase of the study, a consensus pharmacophore was generated based on the optimal conformers of the lead molecule Cu-CPT8m and a second Cu-CPT9b. A series of lead-like molecules were identified, docked into the TLR8 protomol and ranked by affinity. In the de novo phase of the study, seed fragments were modelled, docked into the TLR8 bioactive site and allowed molecular growth within this space. The ligand binding affinity and ligand binding energy of the resultant structures were calculated. The structures with the greatest difference between ligand binding affinity and ligand binding energy were selected as the optimal structures from this molecular cohort. These cohorts from the two methods were analysed and the optimal structures were identified on the basis of ligand binding affinity and pharmacokinetic properties.