Synthesis and characterization of new potent TLR7 antagonists based on analysis of the binding mode using biomolecular simulations

Pal, Sourav; Paul, Barnali; Bandopadhyay, Purbita; Preethy, Nagothy; Sarkar, Dipika; Rahaman, Oindrila; Goon, Sunny; Roy, Supriya; Ganguly, Dipyaman; Talukdar, Arindam

doi:10.1016/j.ejmech.2020.112978

Cited by 8 publications

(35 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous structure-based drug design approach, we demonstrated a universal binding model hypothesis by exploiting a library of all the reported TLR7 antagonists from different chemotypes [41]. Based on our universal model, we displayed the role-specific substituents in TLR7 antagonism, thus, experimentally validating our model.…”

Section: Introductionmentioning

confidence: 70%

“…The important structural attributes responsible for the potent TLR7 antagonistic activities were determined through a ligand-based study including 2D-QSAR, 3D-QSAR, and pharmacophore modeling. The input dataset consisted of a diverse set of 54 small-molecule TLR7 antagonists having different chemotypes, along with their diverse biological activities, from the previously reported literature (Figure S1) [29,32,33,35,41]. All the experimental activity values were collected by following a similar biological assay procedure against the HEK293 reporter cell line.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we combined the steric and electrostatic field effects (derived from 3D-QSAR) as well as the hydrophobic features (from pharmacophore) of quinazoline core com pound 14, for the designing of new compounds with improved antagonistic activity, a shown in Figure 14. We started by employing various substitutions at the C2 and C7 positions of th quinazoline ring, as this scaffold aligned with the pharmacophoric RA and HYA feature (Figure 15 and Figure S4) and is important for hydrophobic π-π interactions with th Tyr356* and Phe408* (* represents the residues of chain B of the homodimeric protein residues in the proposed binding model [41]. We retained the piperazine moiety as Thus, we combined the steric and electrostatic field effects (derived from 3D-QSAR), as well as the hydrophobic features (from pharmacophore) of quinazoline core compound 14, for the designing of new compounds with improved antagonistic activity, as shown in Figure 14.…”

Section: Design Of New Compoundsmentioning

confidence: 99%

“…Thus, we combined the steric and electrostatic field effects (derived from 3D as well as the hydrophobic features (from pharmacophore) of quinazoline co pound 14, for the designing of new compounds with improved antagonistic ac shown in Figure 14. We started by employing various substitutions at the C2 and C7 position quinazoline ring, as this scaffold aligned with the pharmacophoric RA and HYA (Figure 15 and Figure S4) and is important for hydrophobic π-π interactions Tyr356* and Phe408* (* represents the residues of chain B of the homodimeric We started by employing various substitutions at the C2 and C7 positions of the quinazoline ring, as this scaffold aligned with the pharmacophoric RA and HYA features (Figure 15 and Figure S4) and is important for hydrophobic π-π interactions with the Tyr356* and Phe408* (* represents the residues of chain B of the homodimeric protein) residues in the proposed binding model [41]. We retained the piperazine moiety as a useful surrogate at the C4 position of the quinazoline ring because the terminal nitrogen atom of piperazine, being prone to protonation, acted as a hydrogen bond donor.…”

Section: Design Of New Compoundsmentioning

confidence: 99%

“…Since these TLRs are expressed in the acidic (pH 5.5-6.5) endosomal compartment, the molecules must access the target receptor protein located inside the endosomal compartment through their protonated state. We preserved the lipophilic, flexible, three-carbon linker at the C7 position to enhance the extent of the molecules across the hydrophobic pocket and the weak basic amine substituent, which in turn was protonated to engage the positive ionizable feature of the pharmacophore (Figure 15 and Figure S4) [29,41,64]. Thus, we first incorporated electron-donating amino groups on the propylpyrrolidine moiety with lysosomotropic properties, implicating a positive electrostatic potential field (blue grid) that led to compound T63, which probably exhibited significant predicted TLR7 inhibitory activities (Pred_IC 50 : 1 µM) (Table 4).…”

Section: Design Of New Compoundsmentioning

confidence: 99%

See 4 more Smart Citations

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Design Of New Compoundsmentioning

confidence: 99%

Section: Design Of New Compoundsmentioning

confidence: 99%

Section: Design Of New Compoundsmentioning

confidence: 99%

See 3 more Smart Citations

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Synthesis and Structure‐Photophysics Evaluation of 2‐N‐Amino‐quinazolines: Small Molecule Fluorophores for Solution and Solid State

Motoyama

Doan

Hibner-Kulicka

et al. 2021

Chemistry An Asian Journal

View full text Add to dashboard Cite

2‐N‐aminoquinazolines were prepared by consecutive SNAr functionalization. X‐ray structures display the nitrogen lone pair of the 2‐N‐morpholino group in conjugation with the electron deficient quinazoline core and thus representing electronic push‐pull systems. 2‐N‐aminoquinazolines show a positive solvatochromism and are fluorescent in solution and in solid state with quantum yields up to 0.73. Increase in electron donor strength of the 2‐amino substituent causes a red‐shift of the intramolecular charge transfer (ICT) band (300–400 nm); whereas the photoluminescence emission maxima (350–450 nm) is also red‐shifted significantly along with an enhancement in photoluminescence efficiency. HOMO‐LUMO energies were estimated by a combination of electrochemical and photophysical methods and correlate well to those obtained by computational methods. ICT properties are theoretically attributed to an excitation to Rydberg‐MO in SAC‐CI method, which can be interpreted as n‐π* excitation. 7‐Amino‐2‐N‐morpholino‐4‐methoxyquinazoline responds to acidic conditions with significant increases in photoluminescence intensity revealing a new turn‐on/off fluorescence probe.

show abstract

Mitigating hERG Liability of Toll‐Like Receptor 9 and 7 Antagonists through Structure‐Based Design

et al. 2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Synthesis and characterization of new potent TLR7 antagonists based on analysis of the binding mode using biomolecular simulations

Cited by 8 publications

References 49 publications

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

Synthesis and Structure‐Photophysics Evaluation of 2‐N‐Amino‐quinazolines: Small Molecule Fluorophores for Solution and Solid State

Mitigating hERG Liability of Toll‐Like Receptor 9 and 7 Antagonists through Structure‐Based Design

Contact Info

Product

Resources

About