Docking study of triphenylphosphonium cations as estrogen receptor alpha modulators

Joseph P Salisbury,John C Williams

doi:10.6026/97320630003303

Abstract

Virtual high throughput screening (VHTS) was performed to assess possible interactions which might occur between commercially available triphenylphosphonium (TPP) cations and estrogen receptor alpha (ERalpha) that could be exploited to design novel ERalpha modulators. One application of TPP cations is for delivering bioactive molecules to targets in mitochondria as the large membrane potential of mitochondria leads cations to accumulate inside them. The estrogen receptors (ERs) alpha and beta, normally activated by the endogenous hormone 17beta-estradiol, are responsible for controlling transcription of nuclear DNA necessary for human development and reproduction. ERs are also associated with the plasma membrane and have been found in the mitochondria of a variety of cell types. Selective estrogen receptor modulators (SERMs) are synthetic compounds which are used to modulate ER activity. Different SERMs display varying combinations of agonistic, antagonistic and neutral effects upon estrogen receptors depending upon the tissue type and cellular location of the receptor. Thus, they are being employed to treat a range of ER-related disorders. A common feature shared by many SERMs is the close arrangement of three aromatic rings similar to TPP cations. Given this structural similarity, the estrogenic activity of triphenyl phosphonium salts was investigated using the automated docking program eHiTS. Compounds were docked into ten different crystal structures of ERalpha. Structures were chosen based upon eHiTS ability to accurately identify the majority of estrogenically active compounds given a set of active and decoy molecules. The results of the VHTS suggest hybrids of TPP cations and known SERMs could serve as potent mitochondrial SERMs.

Highlights

The estrogen receptors (ERs) α and β are intracellular sites [3]
ER subjected to trauma and hemorrhage and activation of activity is normally modulated by the endogenous hormone mitochondrial ERs having a protective effect on cerebral
Selective mitochondrial ERs have in cellular function would be to estrogen receptor modulators (SERMs) such as tamoxifen design a small molecule which would be capable of and raloxifene have been successful in the treatment and selectively affecting mitochondrial ERs

Summary

Introduction

The estrogen receptors (ERs) α and β are intracellular sites [3]. Current evidence supports mitochondrial proteins responsible for controlling transcription of genes ERβ serving an anti-apopototic role in rat heart muscle necessary for human development and reproduction. To this potential gradient, lipophilic cations, which are able to pass through lipid bilayers due to their dispersed charge, In addition to being found in the nucleus as well as in and are able to accumulate 100-500 fold inside the adjacent to the plasma membrane, ERα and ERβ have mitochondria matrix [5]. This technique has been been located in the mitochondria of a variety of cell types employed to prevent mitochondrial oxidative damage by [2]. E2 has been known to have an inhibitory effect on conjugating anti-oxidants to the triphenylphosphonium apoptosis and mitrochondrial ERs are believed to make a (TPP) cation [6]

Methods

Conclusion