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Estrogen-related receptor α (ERRα) is considered a very promising target for treating metabolic diseases such as type 2 diabetes. Development of a prediction model to quickly identify potential ERRα agonists can significantly reduce the time spent on virtual screening. In this study, 298 ERRα agonists and numerous nonagonists were collected from various sources to build a new dataset of ERRα agonists. Then a total of 90 models were built using a combination of different algorithms, molecular characterization methods, and data sampling techniques. The consensus model with optimal performance was also validated on the test set (AUC=0.876, BA=0.816) and external validation set (AUC=0.867, BA=0.777) based on five selected baseline models. Furthermore, the model's applicability domain and privileged substructures were examined, and the feature importance was analyzed using the SHAP method to help interpret the model. Based on the above, it's hoped that our publicly accessible data, models, codes, and analytical techniques will prove valuable in quick screening and rational designing more novel and potent ERRα agonists., (© 2024 Wiley-VCH GmbH.)

Phenolic environmental endocrine-disrupting chemicals (PEDCs) are persistent EDCs that are widely found in food packaging materials and environmental media and seriously threaten human health and ecological security. Human estrogen-related receptor γ (hERRγ) has been proposed as a mediator for the low-dose effects of many environmental PEDCs; however, the atomic-level descriptions of dynamical structural features and interactions of hERRγ and PEDCs are still unclarified. Herein, how three PEDCs, 4-(1-methylpropyl)phenol (4-sec-butylphenol), 5,6,7,8-tetrahydro-2-naphthol (tetrahydro-2-napthol), and 2,2-bis(4-hydroxy-3,5-dimethoxyphenyl)propane (BP(2,2)(Me)), interact with hERRγ to produce its estrogenic disruption effects was studied. Molecular docking and multiple molecular dynamics (MD) simulations were first conducted to distinguish the detailed interaction pattern of hERRγ with PEDCs. These binding structures revealed that residues around Leu271, Leu309, Leu345, and Phe435 are important when binding with PEDCs. Furthermore, the binding energies of PEDCs with hERRγ were also characterized using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) and solvated interaction energy (SIE) methods, and the results showed that the interactions of CH-π, π-π, and hydrogen bonds are the major contributors for hERRγ binding to these three PEDCs. What is striking is that the methoxide groups of BP(2,2)(Me), as hydrophobic groups, can help to reduce the binding energy of PEDCs binding with hERRγ. These results provide important guidance for further understanding the influence of PEDCs on human health problems.

Breast cancer (BC) is one of the most prevalent cancers in the world and is one of the major reasons for the death of women worldwide. BC is majorly categorized based on the presence or absence of three cell receptors ER, PR and HER2. The latest treatment for BC involves interfering with the production and action of hormones such as estrogen and progesterone. These hormones bind with receptors such as ER and PR and enhance the growth and proliferation of the BC cells. Although the available are effective, the increasing resistance and side effects related to hormonal imbalance are significant and hence there is a need for designing. On the other hand, plant-derivative products have gained a lot of popularity for their promising anti-cancerous activities. Polyphenols are one such group of plant derivatives that have proven to be useful against cancer. In the present study, an in-silico approach was used to search for a polyphenol that can inhibit ER. In this work, a total of 750 polyphenols were taken into consideration. This number was narrowed down to 55, based on their ADMET properties. These 55 polyphenols were then docked to the receptors, ER, PR and HER2. The molecular docking was followed by Molecular Dynamics (MD) simulations. Based on molecular docking and MD simulation results it was concluded that Pseudobaptigenin has the potential to be an inhibitor of ER, PR and HER2.Communicated by Ramaswamy H. Sarma.

Cancer is one of the life-threatening diseases and the second leading cause of death in the world. The estrogen receptor can be considered as one of the significant drug targets for cancer. A large number of clinically used anticancer drugs were identified from phytochemicals. Multiple literatures suggested that extracts of Datura sp. significantly inhibit estrogen receptors associated with human cancer. In the present study, all reported natural products present in Datura sp. were subjected to molecular docking against estrogen receptors. The top hits were shortlisted based on binding orientation and docking score and subjected to molecular dynamics simulation to explore the conformational stability followed by binding energy calculation. The ligand [(1S,5R)-8-Methyl-8-Azabicyclo [3.2.1] Octan-3-yl] (2R)-3-Hydroxy-2-Phenylpropanoate depicts highly acceptable MD simulations outcomes and drug-likeness profile. Knowledge-based de novo design and similar ligand screening were executed using the structural information. The designed ligand DL-50 exhibited satisfactory binding, drug-likeness profile, and well-accepted ADMET profile followed by easy synthetic accessibility which further requires experimental validation., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Estrogen receptor α is commonly used in synthetic biology to control the activity of genome editing tools. The activating ligands, estrogens, however, interfere with various cellular processes, thereby limiting the applicability of this receptor. Altering its ligand preference to chemicals of choice solves this hurdle but requires adaptation of unspecified ligand-interacting residues. Here, we provide a solution by combining rational protein design with multi-site-directed mutagenesis and directed evolution of stably integrated variants in Saccharomyces cerevisiae. This method yielded an estrogen receptor variant, named TERRA, that lost its estrogen responsiveness and became activated by tamoxifen, an anti-estrogenic drug used for breast cancer treatment. This tamoxifen preference of TERRA was maintained in mammalian cells and mice, even when fused to Cre recombinase, expanding the mammalian synthetic biology toolbox. Not only is our platform transferable to engineer ligand preference of any steroid receptor, it can also profile drug-resistance landscapes for steroid receptor-targeted therapies., (© 2024 The Protein Society.)

Tamoxifen, a triphenylethylene-based selective estrogen-receptor modulator, is a landmark drug for the treatment of breast cancer and is also used for treating liver cancer and osteoporosis. Structural studies of tamoxifen have led to the synthesis of more than 20 novel tamoxifen analogs as receptor modulators, including 16 ERα modulators 2-17 , an ERRβ inverse agonist 19 and six ERRγ inverse agonists 20 - 25 . This paper summarizes the research progress and structure-activity relationships of tamoxifen analogs modulating these three nuclear receptors reported in the literature, and introduces the relationship between these three nuclear receptor-mediated diseases and tamoxifen analogs to guide the research of novel tamoxifen analogs.

Zearalenone is an estrogenic mycotoxin which is a common food contaminant and has been implicated in increasing the incidence of carcinogenesis and other reproductive health ailments through the estrogen receptor alpha (ERα) pathway. Competitive ERα blockers such as 4-Hydroxytamoxifen (OHT), are synthetic FDA approved drugs which, albeit being an effective anticancer agent, induces life altering side effects. For this reason, there is an increased interest in the use of naturally occurring medicinal plant products such as flavonoids. This study aimed to identity flavonoid ERα inhibitors and provide insights into the mechanism of inhibition using computational techniques. The Molecular Mechanics/Generalized Born Surface Area calculations revealed that quercetrin, hesperidin, epigallocatechin 3-gallate and kaempferol 7-O-glucoside out of 14 flavonoids had higher binding affinity for ERα than OHT. The structural analysis revealed that the binding of the compounds to the receptor lead to dynamic alterations, which induced conformational shift in the structure and orientation of the receptor resulting in stabilised, compact and low energy systems. The results of this study provide imperative information that supports the use of flavonoids in the inhibition of ERα to prevent or ameliorate the consequential adverse effects associated with zearalenone exposure.Communicated by Ramaswamy H. Sarma.

G protein-coupled receptors (GPCRs) belong to the largest family of protein targets comprising over 800 members in which at least 500 members are the therapeutic targets. Among the GPCRs, G protein-coupled estrogen receptor-1 (GPER-1) has shown to have the ability in estrogen signaling. As GPER-1 plays a critical role in several physiological responses, GPER-1 has been considered as a potential therapeutic target to treat estrogen-based cancers and other non-communicable diseases. However, the progress in the understanding of GPER-1 structure and function is relatively slow due to the availability of a only a few selective GPER-1 modulators. As with many GPCRs, the X-ray crystal structure of GPER-1 is yet to be resolved and thus has led the researchers to search for new GPER-1 modulators using homology models of GPER-1. In this review, we aim to summarize various approaches used in the generation of GPER-1 homology model and their applications that have resulted in new GPER-1 ligands.

Cancer ranks in second place among the cause of death worldwide. Cancer progress in multiple stages of carcinogenesis and metastasis programs through complex pathways. Sex hormones and their receptors are the major factors in promoting cancer progression. Among them, G protein-coupled estrogen receptor-1 (GPER) has shown to mediate cellular signaling pathways and cancer cell proliferation. However, the lack of GPER protein structure limited the search for new modulators. In this study, we curated an extensive database of natural products to discover new potential GPER modulators. We used a combination of virtual screening techniques to generate a homology model of GPER and subsequently used that for the screening of 30,926 natural products from a public database to identify potential active modulators of GPER. The best hits were further screened through the ADMET filter and confirmed by docking analysis. Moreover, molecular dynamics simulations of best hits were also carried out to assess the stability of the ligand-GPER complex. This study predicted several potential GPER modulators with novel scaffolds that could be further investigated and used as the core for the development of novel GPER modulators.Communicated by Ramaswamy H. Sarma.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N , N -dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N , N -dialkylaminoethyl substituent as a privileged functional group for SERMs.

Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and ligand-binding domain (LBD). Estrogenic chemicals work as ligands for activation or repression of ER-mediated transcriptional activity derived from two transactivation domains: AF-1 and AF-2. AF-2 is localized in the LBD, and helix 12 of the LBD is essential for controlling AF-2 functionality. The positioning of helix 12 defines the ER alpha (ERα) ligand properties as agonists or antagonists. In contrast, it is still less well defined as to the ligand-dependent regulation of N-terminal AF-1 activity. It has been thought that the action of selective estrogen receptor modulators (SERMs) is mediated by the regulation of a tissue specific AF-1 activity rather than AF-2 activity. However, it is still unclear how SERMs regulate AF-1 activity in a tissue-selective manner. This review presents some recent observations toward information of ERα mediated SERM actions related to the ERα domain functionality, focusing on the following topics. (1) The F-domain, which is connected to helix 12, controls 4-hydroxytamoxifen (4OHT) mediated AF-1 activation associated with the receptor dimerization activity. (2) The zinc-finger property of the DBD for genomic sequence recognition. (3) The novel estrogen responsive genomic DNA element, which contains multiple long-spaced direct-repeats without a palindromic ERE sequence, is differentially recognized by 4OHT and E2 ligand bound ERα transactivation complexes., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)