Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists.
Sourav PalUddipta Ghosh DastidarTrisha GhoshDipyaman GangulyArindam TalukdarPublished in: Molecules (Basel, Switzerland) (2022)
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 (R 2 training : 0.86 and R 2 test : 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R 2 training : 0.95 and R 2 test : 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 (R training : 0.94 and R test : 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.
Keyphrases
- molecular docking
- toll like receptor
- molecular dynamics
- inflammatory response
- small molecule
- nuclear factor
- molecular dynamics simulations
- immune response
- density functional theory
- binding protein
- oxidative stress
- emergency department
- protein protein
- adverse drug
- dna binding
- multiple sclerosis
- current status
- climate change
- electronic health record