Glu106 targeted inhibitors of ORAI1 as potential Ca²⁺ release-activated Ca²⁺ (CRAC) channel blockers – molecular modeling and docking studies

Abstract

Calcium release-activated calcium modulator 1(ORAI1) is an integral component of the calcium release-activated calcium channel (CRAC) channel complex and plays a central role in regulating Ca^2 +concentrations in T-lymphocytes. It is critical for many physiological processes, including cell-proliferation, cytokine production and activation of the immune system. Loss of ORAI1 function is linked with rheumatoid arthritis (RA) and hence pharmacological blockers of ORAI1 could be potential therapeutic agents for the treatment of RA. In this study, we have used a high-throughput screening approach to inhibit the binding of Ca²⁺toward ORAI1 and the interactions are verified through induced fit docking. The results hint that these compounds act by possibly binding with, and thereby blocking Ca²⁺-binding with ORAI1 (E106). The molecular dynamics (MD) simulations shows strong support toward the hit compounds by showing the ligand potency throughout the simulation timescale of 30 ns. We have thus identified a novel class of highly stable, potential lead compounds that directly bind with the selectivity filter region E106 and block Ca²⁺ binding on ORAI1. This resulting alteration in the pore geometry of ORAI1 due to the strong blocking mechanism of lead compounds will greatly diminish its function and the downstream activities that result from the same including decreased production of cytokines in autoimmune disorders. This study may lay the foundation for finding novel lead compounds for clinical trials that could positively modulate the course of autoimmune disorders with ORAI1 as its specific target.

• Rheumatoid arthritis
• CRAC channel
• ORAI1 inhibitors
• virtual screening
• molecular docking
• molecular dynamic simulation

Acknowledgements

The authors thankfully acknowledge Dr. D J Rayalu, Global Biotech solutions for providing the software support.

S.B. thankfully acknowledges the Department of Science and Technology (DST), New Delhi, India, for providing an INSPIRE Fellowship (Ref Number: IF130100).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Supplementary material available online