Screening approaches against claudin-4 focusing on therapeutics through molecular docking and the analysis of their relative dynamics: a theoretical approach

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.

Keywords:

• Claudin-4 inhibitor
• Asinex screening
• molecular docking
• dynamic simulations
• ADME

Acknowledgments

The authors would like to thank the management of Vellore Institute of Technology, Vellore for providing necessary support for carrying out this research work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors are thankful for the financial support from the Department of Science and Technology – Science and Engineering Research Board (DST-SERB) [SB/YS/LS-299/2013].