title: 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 Ca2 +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.
authors.affiliation: a Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology, Anna University , Chennai , Tamil Nadu , India.
authors.forename: Bhuvaneshwari
authors.initials: B
authors.lastname: Sampath
authors.affiliation: a Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology, Anna University , Chennai , Tamil Nadu , India.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sankaranarayanan
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D000071739:Calcium Release Activated Calcium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007854:Lead / Q000737:chemistry* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000187:drug effects; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000071740:ORAI1 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D000071739:Calcium Release Activated Calcium Channels; D008565:Membrane Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D007854:Lead; D002118:Calcium
keywords: CRAC channel; ORAI1 inhibitors; Rheumatoid arthritis; molecular docking; molecular dynamic simulation; virtual screening