Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists
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 ther...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/13/4026 |
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| author | Sourav Pal Uddipta Ghosh Dastidar Trisha Ghosh Dipyaman Ganguly Arindam Talukdar |
| author_facet | Sourav Pal Uddipta Ghosh Dastidar Trisha Ghosh Dipyaman Ganguly Arindam Talukdar |
| author_sort | Sourav Pal |
| collection | DOAJ |
| description | 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<sup>2</sup><sub>training</sub>: 0.86 and R<sup>2</sup><sub>test</sub>: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R<sup>2</sup><sub>training</sub>: 0.95 and R<sup>2</sup><sub>test</sub>: 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<sub>training</sub>: 0.94 and R<sub>test</sub>: 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. |
| first_indexed | 2024-03-09T04:01:36Z |
| format | Article |
| id | doaj.art-82c1606dfae747dda71ec559fed1d90f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:01:36Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-82c1606dfae747dda71ec559fed1d90f2023-12-03T14:12:58ZengMDPI AGMolecules1420-30492022-06-012713402610.3390/molecules27134026Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 AntagonistsSourav Pal0Uddipta Ghosh Dastidar1Trisha Ghosh2Dipyaman Ganguly3Arindam Talukdar4Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaDepartment of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaDepartment of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaIICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata 700091, IndiaDepartment of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaToll-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<sup>2</sup><sub>training</sub>: 0.86 and R<sup>2</sup><sub>test</sub>: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R<sup>2</sup><sub>training</sub>: 0.95 and R<sup>2</sup><sub>test</sub>: 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<sub>training</sub>: 0.94 and R<sub>test</sub>: 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.https://www.mdpi.com/1420-3049/27/13/4026drug designQSARpharmacophore modelmolecular dynamicsTLR7 antagonists |
| spellingShingle | Sourav Pal Uddipta Ghosh Dastidar Trisha Ghosh Dipyaman Ganguly Arindam Talukdar Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists Molecules drug design QSAR pharmacophore model molecular dynamics TLR7 antagonists |
| title | Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists |
| title_full | Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists |
| title_fullStr | Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists |
| title_full_unstemmed | Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists |
| title_short | Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists |
| title_sort | integration of ligand based and structure based methods for the design of small molecule tlr7 antagonists |
| topic | drug design QSAR pharmacophore model molecular dynamics TLR7 antagonists |
| url | https://www.mdpi.com/1420-3049/27/13/4026 |
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