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Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
Screening approaches against claudin-4 focusing on therapeutics through molecular docking and the analysis of their
Majji Rambabu1, Sivaraman Jayanthi1
1Department of Biotechnology, Vellore Institute of Technology, Vellore, India.
Abstract:
Claudin-4 (CLDN4) is a class of transmembrane protein in the family of tight junction (TJ) proteins. Overexpression of CLDN4 is reported in the case of ovarian cancer and epithelial malignancies. The current study is focused on the identification of lead compounds for CLDN4 adopting the structure-based drug design method. The Schrodinger glide is used as a molecular docking tool for the initial docking of CLDN4 with Asinex Database by performing high throughput virtual screening, top hits were identified. Then, compounds BDF 33196188 and BDE 30874918 were identified by molecular docking based on binding energy in the active site of CLDN4. Subsequently, critical residues were identified such as Asp146 and Arg158 with the least binding energy from Extra Precision method. Further, molecular dynamics simulations of claudin-4 protein were used for the optimization of best ligands with claudin-4 in a dynamic system. Molecular docking and molecular dynamics simulations predicted critically important residues ASP146 and ARG158 involved in claudin-4 binding. The hits retrieved from screening were docked into protein by relevant procedures including HTVS, SP, and XP. Finally, two molecules were identified as potential claudin-4 inhibitors. The two ligands BDF 33196188 and BDE 30874918 are suggested as potential inhibitors for CLDN4. In summary, our computational strategy established novel leads against CLDN4 from Asinex Database and recommended as anti-cancer agents.
Insights
Researchers identified potential anti-cancer agents by screening for Claudin-4 (CLDN4) inhibitors. Computational methods pinpointed two lead compounds, BDF 33196188 and BDE 30874918, targeting CLDN4 for ovarian cancer and epithelial malignancies.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Chemistry
- Drug Discovery
Background:
- Claudin-4 (CLDN4) is a transmembrane protein crucial for tight junctions.
- CLDN4 overexpression is linked to ovarian cancer and other epithelial malignancies, making it a therapeutic target.
Purpose of the Study:
- To identify novel lead compounds that inhibit Claudin-4 (CLDN4) using structure-based drug design.
- To computationally screen for potential anti-cancer agents targeting CLDN4.
Main Methods:
- High-throughput virtual screening using Schrodinger glide for docking CLDN4 with the Asinex Database.
- Molecular docking and molecular dynamics simulations to identify lead compounds and critical binding residues (Asp146, Arg158).
- Utilized docking procedures including High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP).
Main Results:
- Identified two lead compounds, BDF 33196188 and BDE 30874918, with significant binding energy in the CLDN4 active site.
- Molecular dynamics simulations confirmed the binding of these ligands and highlighted the involvement of Asp146 and Arg158 residues.
- The study successfully established novel CLDN4 inhibitors from the Asinex Database.
Conclusions:
- BDF 33196188 and BDE 30874918 are proposed as potential inhibitors of CLDN4.
- The computational strategy effectively identified promising anti-cancer agents targeting CLDN4 for further development.
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