Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method

Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, a calcium channel overexpressed in breast and prostate cancer, and its use to test the effect of blocking TRPV6-mediated Ca2+-influx on cell growth. The inhibitor was discovered through a computational method, xLOS, a 3D-shape and pharmacophore similarity algorithm, a type of ligand-based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule, two successive rounds of LBVS followed by optimization by chemical synthesis led to a selective molecule with 0.3 μM inhibition of TRPV6. The ability of xLOS to identify different scaffolds early in LBVS was essential to success. The xLOS method may be generally useful to develop tool compounds for poorly characterized targets.

Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors.

In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case-control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised.