Cardiac hypertrophy results in the higher rate of heart failures among aged groups. Klotho is an anti-aging protein that is involved in the regulation of VEGF-mediated Ca2+ entry by direct interaction with Vascular endothelial growth factor receptor 2 (VEGFR2) and transient receptor potential canonical Ca2+ channel 1 (TRPC1). Here, in this study, through in silico analysis, we modeled TRPC1 3-dimensional structure and followed by its optimization, characterized the interaction pattern of TRPC1, Klotho and VEGFR2. Subsequent molecular dynamics (MD) simulation analysis revealed that Klotho-specific (P520-N630) region exhibited interaction with VEGFR2, while its C-terminal region (I822-A931) demonstrated binding to the 3rd extracellular loop of TRPC1 that is adjacent to pore region. Through TRPC1 homotetramer formation, the residues in the periphery of pore region were carefully evaluated. In order to scrutinize known Ca2+ channel blockers for their ability to bind at the pore region of TRPC1, 31 known compounds were tested through docking runs and three hits, named as diltiazem impurity B (b3), diltiazem (b5) and felodipine (b6) were selected for detailed binding analysis through MD runs. Evidently, inhibitor-bound TRPC1 pore area was more constricted (8.6 Å2, 25.1 Å2 and 18.8 Å2, respectively) than apo-TRPC1 (60 Å2). These findings suggest that Ca+2 channel blockers may serve as promising agents to impair the TRPC1 functional store-operated calcium channel (SOCC) activity in the old patients lacking Klotho expression. Thus, pore region of homotetrameric TRPC1 may be blocked via repurposing of known Ca+2 blockers to antagonize TRPC signaling for the treatment of cardiac hypertrophy.
Keywords: Ca(+2) channel blockers; Cardiac hypertrophy; Klotho; Molecular dynamics simulation; TRPC1; VEGFR2.
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