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Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists.
- Source :
-
Molecules . Jul2022, Vol. 27 Issue 13, p4026-N.PAG. 40p. - Publication Year :
- 2022
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 27
- Issue :
- 13
- Database :
- Academic Search Index
- Journal :
- Molecules
- Publication Type :
- Academic Journal
- Accession number :
- 157998088
- Full Text :
- https://doi.org/10.3390/molecules27134026