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Research Article

Structural and accessibility studies highlight the differential binding of clemizole to TRPC5 and TRPC6

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Received 10 Oct 2023, Accepted 07 Jan 2024, Published online: 27 Jan 2024
 

Abstract

Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led to extensive searches for their inhibitors. Although several potent T RP C inhibitors have been developed and the structure of their binding sites were mapped using cryo electron microscopy, a comprehensive understanding of the molecular interactions within the inhibitor binding site of T RP Cs remains elusive. This study aimed to decipher the structural determinants and molecular mechanisms contributing to the differential binding of clemizole to T RP C5 and T RP C6, with a particular focus on the accessibility of binding site residues. This information can help better understand what molecular features allow for selective binding, which is a key characteristic of clinically effective pharmacological agents. Using computational methodologies, we conducted an in-depth molecular docking analysis of clemizole with T RP C5 and T RP C6 channels. The protein structures were retrieved from publicly accessible protein databases. Discovery Studio 2020 Client Visualizer and Chimera software facilitated our in-silico mutation experiments and enabled us to identify the critical structural elements influencing clemizole binding. Our study reveals key molecular determinants at the clemizole binding site, specifically outlining the role of residues' Accessible Surface Area (ASA) and Relative Accessible Surface Area (RASA) in differential binding. We found that lower accessibility of T RP C6 binding site residues, compared to those in T RP C5, could account for the lower affinity binding of clemizole to T RP C6. This work illuminates the pivotal role of binding site residue accessibility in determining the affinity of clemizole to T RP C5 and T RP C6. A nuanced understanding of the distinct binding properties between these homologous proteins may pave the way for the development of more selective inhibitors, promising improved therapeutic efficacy and fewer off-target effects. By demystifying the structural and molecular subtleties of T RP C inhibitors, this research could significantly accelerate the drug discovery process, offering hope to patients afflicted with T RP C-related diseases.

Acknowledgements

The authors thank the Department of Life Science, DAVV for facilities.

Authors contribution

Uzma Saqib: Conceptualization, Funding acquisition, Methodology, Writing - original draft. Issac S. Demaree: Formal analysis, Methodology, Writing—Review & editing. Alexander G. Obukhov: Methodology, Writing - original draft. Mirza S. Baig: Methodology, Writing - original draft. Mohd Shahnawaz Khan: Formal analysis, Methodology, Visualization, Writing—Review & editing. Funding acquisition Nojood Altwaijry: Formal analysis, Methodology, Visualization, Writing—Review & editing. Funding acquisition, Mochammad Arfin Fardiansyah Nasution: Methodology, Visualization, Writing—Review & editing. Kenji Mizuguchi: Methodology, Resources, Writing—Review & editing. Krishnan Hajela: Conceptualization, Supervision, Writing - original draft.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

U.S. gratefully acknowledges financial assistance from UGC-DSKPDF (BL/20-21/0482 (S-90)). A.G.O. was supported by an NIH grant (NS102415). M.S.K. acknowledges the generous support from the Research Supporting Project (RSP2024R352) by King Saud University, Riyadh, Kingdom of Saudi Arabia.

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