Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies.

BACKGROUND: Endometriosis is a complex and polygenic disease characterized by the growth of endometrial-like tissue outside the uterus. Associated conditions include pelvic pain and infertility among others. Current treatments of endometriosis are not effective in many patients and are prone of side effects, being laparoscopy the main solution for them. However, laparoscopy is an invasive solution that can negatively affect ovarian reserve among others fertility consequences. Therefore, more effective treatments are needed for inhibiting the disease progression. Some approaches as systems pharmacology can offer new avenues to study complex diseases at a systematic level, allowing us the integration of information at different levels for prioritizing effective therapies. OBJECTIVE: To use systems pharmacology and in vitro analyses to predict more effective endometriosis treatment among approved drugs on the market for further clinical trials. STUDY DESIGN: Data-driven discovery study integrating protein-protein interactions, transcriptomics, approved drugs and endometriosis-related gene targets to predict therapies that can be repositioned in endometriosis. An in-silico molecular drug efficacy screening was performed to compare proposed treatments with the current ones. The candidate drugs with the safest clinical profiles were prioritized for in-vitro validation in an endometriosis cell model. RESULTS: Our endometriosis molecular model showed that the endometriosis progression and the infertility associated are molecularly highly related since they share 210 genes through direct protein-protein interactions from 553 infertility-related and 2,931 progression-related endometriosis genes, an overlap that is higher than randomly expected (p-value = 1.9 × 10⁻¹¹). In addition, these genes are also closer physically interacting in the network than random expectation (z-score = −1.75, p-value = 0.03). Both results highlighted the similar molecular basis of endometriosis progression and infertility associated to endometrium. Leveraging this endometriosis disease network, we have identified sixteen potential candidate drugs, which had a superior molecular efficacy treating the disease genes as they target more endometriosis-related genes (p-value = 0.01) than randomly expected compared with current endometriosis treatments (p-value = 0.97). The drug safety analysis deemed adenine, copper, zinc, NADH, glutathione, and resveratrol as the safest candidate drugs for endometriosis, with no or hardly any clinical side effects. Zinc, copper and resveratrol suppressed endometriosis-related phenotypes in 12Z cells, including cell proliferation, migration, and overexpression of endometriosis-related biomarkers ( ERB , IL-6 and VEGF) . CONCLUSION: This approach highlights the nutraceutics zinc and copper for having superior molecular efficacy than current endometriosis treatments, no considerable side effects, and the ability to reduce endometriosis cell phenotypes. Long-term clinical trials will be needed to confirm women in vivo effectiveness and provide new treatment opportunities for refractory endometriosis. Condensation page: Tweetable Statement: A drug repurposing approach based on systems pharmacology and in vitro validation predict that zinc and copper nutraceuticals target 76 endometriosis-related genes, reverse endometriosis phenotypes, and exceed efficacy of current treatments AJOG at a Glance: A. Why was this study conducted?: Current endometriosis treatments do not effectively address root causes of the disease and have side effects. Systems pharmacology-based models help uncover existing drugs that can be repurposed for complex diseases such as endometriosis. B. What are the key findings?: A systems pharmacology-based model prioritized sixteen approved pharmacotherapies with superior molecular efficacy than current endometriosis therapies. Experimental validation of three of the safest prioritized compounds (resveratrol, copper, and zinc) showed a significant reduction of endometriotic cell phenotypes. C. What does this study add to what is already known?: There are several opportunities to improve the standard of care for patients suffering endometriosis with existing drugs on the market. Multi-target pharmacotherapies are likely more effective and safer than current endometriosis treatments and surgical interventions.