Estetrol: A New Choice for Contraception

Estetrol (E4) is a natural estrogenic steroid that is normally produced by human fetal liver. Recent research has demonstrated that it is a potent, orally bioavailable, natural selective estrogen receptor modulator; it has a moderate affinity for both human estrogen receptor alpha (ERα) and ERβ, with a preference for ERα. Clinical studies have demonstrated possible use as an estrogen in combined oral contraceptives (COC). COCs containing E4 and drospirenone (DRSP) showed a high acceptability, tolerability, and user satisfaction also when compared to COCs containing ethinylestradiol (EE). E4/DRSP effectively inhibits ovulation, with a similar effect on endometrium thickness than that of EE-containing COCs. Low doses (15 mg) of E4 with DRSP (3 mg) showed promising results in term of bleeding pattern and cycle control, also when compared to other COCs containing synthetic estrogens. Moreover, the association has limited effects on serum lipids, liver, SHBG levels, and carbohydrate metabolism. This combination also could drive a lower risk of venous thromboembolism than EE-containing COCs. In this review, we will summarize the actual knowledge about the new E4-containing contraceptive. Further large-scale studies in the full target population are needed to provide more insights into the cardiovascular safety profile and user satisfaction of E4/DRSP.

Design of Novel Selective Estrogen Receptor Inhibitors using Molecular Docking and Protein-Ligand Interaction Fingerprint Studies

Aims: The genomic and non-genomic actions of human estrogen receptor α (hERα) play a crucial role in breast epithelial cell proliferation and survival, as well as mammary tumorigenesis. hERα has been proved as a potential target for breast cancer therapy over the last 3 decades. Hence designing novel inhibitors targeting hERα can be a valuable approach in breast cancer therapy. Study Design: In the present study, the goal is to identify novel hERα inhibitors through molecular docking, AI based virtual screening and interaction fingerprint analysis. Place and Duration of Study: Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India in between July 2021-sep 2021. Methodology: Molecular docking studies were performed using the human estrogen receptor alpha ligand-binding domain in complex with 4-hydroxytamoxifen (PDB: 3ERT) against existing compounds from literature. The best docked existing compound and co-crystal ligand were subjected to shape screening against 28 million compounds and resulted compounds constituted the hERα inhibitor dataset which was subjected to rigid receptor docking. Further, interaction fingerprint analysis was applied as complimentary method to docking for comparing the similarity of predicted binding poses of proposed leads with that of reference binding pose. Results: Co-crystal ligand (4-OHT) and E99 exhibited better binding affinity among existing ligand set. Rigid receptor docking studies resulted in four lead compounds possessing better docking scores than 4-OHT and E99. Moreover, leads showed favorable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95% FDA approved drugs. Proposed leads showed interactions with binding site residues of hERα similar to that of 4-OHT with better binding affinity. The ability of obtained leads to retrieve actives was validated using receiver operative characteristic (ROC) curve. Conclusion: From above results, it has been observed that the proposed leads have potential to act as novel hERα inhibitors.

The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice

Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER). It is able to decrease the size of xenografted human breast tumors, in mice. As GPER has been reported to participate in pain and inflammation, we were interested in exploring the potential of ERα17p in this respect. We observed that the peptide promoted anti-hyperalgesic effects from 2.5 mg/kg in a chronic mice model of paw inflammation induced by the pro-inflammatory complete Freund’s adjuvant (CFA). This action was abrogated by the specific GPER antagonist G-15, leading to the conclusion that a GPER-dependent mechanism was involved. A systemic administration of a Cy5-labeled version of the peptide allowed its detection in both, the spinal cord and brain. However, ERα17p-induced anti-hyperalgesia was detected at the supraspinal level, exclusively. In the second part of the study, we have assessed the anti-inflammatory action of ERα17p in mice using a carrageenan-evoked hind-paw inflammation model. A systemic administration of ERα17p at a dose of 2.5 mg/kg was responsible for reduced paw swelling. Overall, our work strongly suggests that GPER inverse agonists, including ERα17p, could be used to control hyperalgesia and inflammation.

Docking Investigation on Bis (Nitro Indazolyl) Methanes; Synthesis and Antimicrobial Activity Towards Breast Cancer Applications

: Bismuth (III) nitrate pentahydrate (BN) was found to be a mild and efficient catalyst for the electrophilic condensation of 5-nitroindazole with a wide range of aldehydes to obtain Bis (5-nitro indazolyl) methanes 3 (a-h) at ambient temperature. This was structurally confirmed from FTIR, NMR, and HR-MS technique. Molecular docking studies of all compounds was carried out using breast cancer-causing human estrogen receptor (ER) from Molegro Virtual Docker software. Hydroxy Bis (nitro indazolyl) methanes (3b) were shown better binding affinities and the score obtained was -150.146 Kcal/mol compared with Tamoxifen drug. The major H-bond interactions were observed with the compound 3f and the value was -5.679. The antimicrobial activity results revealed that compounds 3b and 3d showed promising activity against bacteria Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Pseudomonas aeruginosa and maximum inhibition against Aspergillus niger and Aspergillus flavus. Methoxy derivatives of Bis (nitro indazolyl methanes) (3e) have shown better antioxidant activity and low MIC (6.25 µg/ml) observed for the compounds 3a and 3b. The synthesized compounds have a very promising starting point for the development and improvement of anti-breast cancer drugs.

SARS-CoV2 S Protein Features Potential Estrogen Binding Site

Research background: During the current SARS-CoV2 pandemic, as well as earlier SARS and MERS epidemics, it has been observed that COVID19-positive women on average tend to have milder symptoms and lower fatality rates than men. There is a number of differences between sexes known to contribute to different immune responses and severity of disease, one being the effect of estrogen via estrogen receptor signaling. We wondered if estrogen might also affect the SARS-CoV2 more directly, perhaps by binding to the surface glycoprotein (S protein) thus possibly reducing its infectivity. Experimental approach: To assess whether there is a possibility for estrogen binding on the SARS-CoV2 S protein we used BLAST and HHpred to compare protein sequences of S protein and human estrogen receptor β, while 3D structures of potential estrogen binding site and active site of estrogen receptor β were visualized and compared using PyMOL. Results and conclusions: By comparing protein sequence of SARS-CoV2 S protein with the human estrogen receptor β, we identified a potential estrogen binding site on S protein and further determined that it also shares notable similarities with the active site of ER β when observed in 3D structure of their respective proteins. As a control, SARS-CoV2 S protein was compared with the human androgen receptor, and no such similarities were found. The potential estrogen binding site is a part of coronavirus S2 superfamily domain, which is involved in host-virus membrane fusion during infection and appears to be conserved throughout the Coronaviridae family. Novelty and scientific contribution: This preliminary communication shows that SARS-CoV2 S protein features a potential estrogen binding site. Hopefully, this will prompt a more comprehensive study on the possibilities of estrogen binding on the S protein and the effect this might confer on the virus infectivity.