Estrogen Receptors: Molecular Interactions, Virtual Screening and Future Prospects

Abstract

Identification of the Estrogen Receptor (ER) as a key mediator of the proliferation of breast cancer, and its involvement in pathways leading to osteoporosis and coronary heart disease, has resulted in a surge to discover and design compounds with the ability to modulate its actions (SERMs). Concurrently, a dramatic increase in the number of crystal structures of the ER has led to a more in depth understanding of the governing mechanisms involved in ER modulation. Entwining computational techniques with the availability of 3D structural data, has allowed not only the rational design of potent inhibitors of the ER, but also its incorporation in Virtual Screening (VS) in the search for novel chemotypes that can modulate the ER. An important initial step in the VS process is to filter towards molecules that occupy similar chemical space to a set of known actives prior to docking. We illustrate through Principal Component Analysis (PCA) of 145 descriptors the region of chemical space antiestrogens occupy compared with 'drug-like' space. We also review all available studies involving validation of several docking algorithms utilizing the ER, ultimately focusing on analysis of Enrichment (E) rates and False Positive (FP) rates to illustrate the successes attributed to each docking algorithm. Finally, we relate the recent discovery of non-genomic mechanisms of the ER and subsequently present a model involving a recently identified alternative, second binding-pocket of the ER in our laboratory through cavity analysis that suggests how the same receptor can invoke these, 'classical' and rapid responses concurrently.

Target Specific Virtual Screening: Optimization of an Estrogen Receptor Screening Platform

“…As discussed elsewhere, 23 the key to turning an estrogenic substance into an antiestrogen is by inclusion of a basic sidechain such as that of a dimethylaminoethyl chain of tamoxifen. It is interesting to note that none of the compounds possessed the predicted ability to interact directly (i.e., via H-bonding) with what is usually considered to be the key antiestrogenic residue, Asp351, but yet they all exhibited inhibitory activity close to that of tamoxifen.…”

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

“…A set of atom-centered RHF 6-31G* charges was then obtained by using the RESP methodology. [71] The X-ray crystal structure of E. electricus acetylcholinesterase was retrieved from the Protein Data Bank (PDB ID: 1C2B) [72] as target protein. Missing atoms were reconstructed with SwissPDB Viewer 4.1.0.…”

The ins and outs of GPR30: A transmembrane estrogen receptor

“…Ligand-based virtual screening, which uses no input from the presumed receptor target, was used since steroid receptors as a class are particularly approachable resulting from the fact that their endogenous ligands (e.g., estradiol, testosterone, progesterone, cortisol) are very rigid in structure. This leaves no room for speculation regarding flexibility of the bioactive ligand conformation [42]. Using this approach, we selected the top 100 compounds (out of a library of almost 10,000) that resembled 17β-estradiol in shape, chemical structure similarity and pharmacophoric pattern.…”