A. Seven essential proteins are associated with menstrual irregularities/disorders in SVD-CCA analysis. They are: glucocorticoid receptor (NR3C1); glucocorticoid Nuclear Receptor 2(NCOA2), progesterone-receptor (PGR), retinoic-acid-receptor (RARA), estrogen-receptor (ESR2), Janus kinase 2 (JAK2), vascular endothelial growth factor 2 (VEGFR2). Experimental assays in our IC50 Assay Dataset confirmed binding between six pairs of essential proteins and drugs (red edge): tamoxifen to NCOA2 and JAK2, dexamethasone to NCOA2 and JAK2 and dasatinib to JAK2 and VEGFR2. Experiments conducted by Novartis reveal ten proteins associated with menstrual irregularities. Four of them are the same with our predicted ones (orange highlight): estrogen-receptor (ESR2), progesterone-receptor (PGR), glucocorticoid receptor (NR3C1) and vascular endothelial growth factor 2 (VEGFR2).
B. Proteins associated with hypocalcemia in SVD-CCA analysis
They are: apolipoprotein (APOD), DNA polymerase beta (POLB), histone deacetylase 8 (HDAC8), hypoxia-inducible factor 1-alpha inhibitor (FIH1), glyoxalase I (GLO1), matrix metalloproteinase-3 (MMP3), matrix metalloproteinase-7 (MMP7), peroxisome proliferator-activated receptor alpha (PPARA), sex steroid-binding protein (SBP) and vitamin D3 receptor (VDR). One survey reported two proteins to be associated with hypocalcemia: calcium-sensing receptor (CASR) and vitamin D3 receptor(VDR). Naturally occurring mutations in the calcium-sensing receptor gene (CASR) cause hypocalcaemia or hypercalcemia. In knockout mice, genetic inactivation of VDR leads to hypocalcemia. We have predicted VDR as an important protein that may interact with saquinavir (HIV drug) and three cancer drugs. In addition, ganciclovir is known to interact with POLB and saquinavir binds to PPARA. Since hypocalcemia is a side effect for many drugs, the predicted essential proteins bound may provide insights into diverse mechanisms of hypocalcemia.