Table 3:
Features from chemical and biological data sources that have a particularly high significance in the difference of distributions for the three DICT Concern Categories (Most, Less, No-concern).
| Feature | P-value (statistical test) | Test applied | Feature space | Description/Biological interpretation | Source |
|---|---|---|---|---|---|
| Cmax (total) | 2.97e-04 | Mann Whitney Wilcoxon test two-sided with Bonferroni correction (most vs. no) | Pharmacokinetic parameters30 | The peak total concentration of a drug in plasma indicates how much of the drug reaches the bloodstream. | 55 |
| Cmax (unbound) | 7.58e-04 | The peak unbound (active) concentration of a drug in plasma, indicates how much of the drug is available for interaction with its target. | |||
| Cyclooxygenase inhibitor | 2.98e-06 | Chi-squared test | MOA (Drug Repurposing Hub29) | Inhibits cyclooxygenase enzymes, often leading to reduced inflammation but also increased blood pressure. | 57 |
| Tyrosine kinase receptor inhibitor | 3.24e-05 | Inhibition of tyrosine kinase receptors can affect cell growth and proliferation and can also induce endoplasmic reticulum stress, hypertension, heart failure, myocardial infarction, and cardiac arrhythmias. | 58 | ||
| PDGFR tyrosine kinase receptor inhibitor | 3.24e-05 | ||||
| PTGS2 | 9.67e-07 | Chi-squared test | Known targets (Drug Repurposing Hub29) | Prostaglandin-endoperoxide synthase 2 (an enzyme) also known as COX-2. | 57 |
| PTGS1 | 9.67e-07 | Prostaglandin-endoperoxide synthase 1 (an enzyme) also known as COX-1. | |||
| HTR1D | 1.27e-05 | 5-hydroxytryptamine receptor 1D, a serotonin receptor subtype. Previous enrichment analysis for methylation differences identified HTR1D among the genes with decreased promoter methylation, suggesting its involvement with serotonin receptors, which influences human cardiac function | 63,64 | ||
| Q12809 at 100uM (KCNH2) (hERG) | 1.21e-18 | Kruskal-Wallis test Chi-squared test | CellScape Predicted Target34 | The hERG gene encodes Kv11.1 channels crucial for heart function, linked to genetic and drug-induced arrhythmias | 59 |
| Cytoplasm Granularity 2 ER | 4.64e-04 | Cell Painting24 | Fine-grained smoothness of the ER staining. Disruptions in ER function can lead to ER stress, which is associated with various cardiovascular diseases. | 65 | |
| Cells Granularity 2 ER | 1.05e-03 | ||||
| Nuclei Texture Contrast RNA 3 0 | 1.19e-03 | Contains information about the size, shape, number, or texture of nucleoli within the nucleus. This could encode signals for cellular stress. | 66 | ||
| 222103 at (ATF1) | 1.01e-04 | Gene Expression19,25 | ATF1 is essential for cardiomyocyte function. | 67 | |
| 201080 at (PIP4K2B) | 6.29e-04 | The role of PIP4k2 in cardiac disorders remains uncertain. PIP4Ks regulate insulin production and immune response, with PIP4k2c impacting TGFβ1 signaling which is vital in heart disease and other fibrotic conditions. | 68 | ||
| 209092 s at (GLOD4) | 8.14e-04 | The physiological function of GLOD4 remains largely unexplored. The glyoxalase gene family, comprising six enzymes with roles in metabolism and disease prevention, is crucial for detoxifying reactive dicarbonyls and maintaining cellular homeostasis. | 69 | ||
| transport vesicle (GO:0030133) | 5.53e-04 | Gene Ontology19,26 | Extracellular vesicles play important roles in cardiovascular communication, transporting bioactive molecules that both maintain heart health and contribute to cardiovascular diseases. | 70 | |
| negative regulation of potassium ion transmembrane transport (GO:1901380) | 1.04e-03 | Cardiac K+ channels play a crucial role in cardiac repolarization and their dysfunction can lead to arrhythmias. | 71 | ||
| response to methylmercury (GO:0051597) | 1.56e-03 | Exposure to mercury (Hg) is considered to be an increased risk of developing cardiovascular system | 72 | ||
| VSA EState6 | 6.67e-09 | Physicochemical Descriptors from RDKit36 | VSA EState Descriptor 6 (6.00 <= x < 6.07) related to molecular surface area and electronic state. | 73 | |
| Qed | 1.20e-07 | Quantitative estimate of drug-likeness, a measure indicating how drug-like a molecule is. | 74 | ||
| NumHAcceptors | 1.26e-07 | Number of hydrogen bond acceptors in the molecule. | 75 |