Current Medicinal Chemistry, Volume 12, No. 9, 2005
Contents
Steroid
Nuclear Receptor Family
Guest
Editor: Pedro H.H. Hermkens
Editorial Pp. 999-999
Pedro H.H. Hermkens
The Nuclear Receptor Ligand-Binding Domain: A
Family-Based Structure Analysis
Pp. 1001-1016
Simon Folkertsma, Paula I. van Noort, Ralph F.J. Brandt,
Emmanuel Bettler, Gerrit Vriend and Jacob de Vlieg
Non-Steroidal Steroid Receptor Modulators Pp. 1017-1075
Rogier C. Buijsman, Pedro H.H. Hermkens, Rachel D. van
Rijn, H. Thijs Stock and N. Miranda Teerhuis
Non-Steroidal Subtype Selective Estrogens Pp. 1077-1136
Gerrit H. Veeneman
Abstracts
[Back to top] Editorial
This special issue reviews in three constitutive papers some recent developments in the area of the nuclear receptor family. Nuclear receptors (NRs) are ligand-dependent transcription factors that play a central role in various physiological processes. The pharmaceutical industry has great interest in this gene-family for the discovery of novel or improved drugs for treatment of, for example, cancer, infertility, or diabetes.
Leading off, de Vlieg et al. overviews a family based structure analysis of the Nuclear Receptor Ligand-Binding Domain. The usage of three-dimensional coordinates of protein structures to analyse and predict interactions with ligands is an important aspect of this process. All NR ligand-binding domains have a similar fold, which allows for comparison of the structures of their three main functional sites: the ligand-binding pocket, the cofactor-binding groove, and the dimerization interface. Described is an analysis of nearly one hundred NR ligand-binding domain structures. Hermkens et al. reviews non-steroidal Receptor Modulators of the PR, GR,AR, FXR and LXR receptors. Because of three reasons, the last ten years much attention has been focussed on the finding of non-steroidal ligands for these steroidal receptors. Firstly, synthetic steroidal ligands designed to interact with these receptors have the downside that they also often bind to structurally closely related steroid receptors. This cross-reactivity is often the reason for side effect profiles. Secondly, different chemotypes have different properties (i.e. PK, physicochemical parameters and ADMET profiles) which might cause different tissue distribution profiles and therefore differences in functionality with respect to steroid ligands. Thirdly, it has been demonstrated that binding of different chemotypes to the ligand binding pocket might cause differences in the orientation of key structural elements which are involved into the binding of cofactors and therefore change the relative equilibrium between affinities of these proteins. ncreased or decreased binding to cofactors is the key rationale for functional selectivity. Compounds with a selective functionality profile are referred to as selective nuclear receptor modulators (e.g., SERMs, SARMs, SPRMs). Finaly, Veeneman reviews the topic non-steroidal subtype selective estrogens. The substantial efforts for over 40 years to design non-steroidal estrogens have resulted in the disclosure of hundreds of different ligands. A special category of estrogens are the so-called selective estrogen receptor modulators (SERMs), comprising a class of non-steroidal estrogens that mimic estrogen in some tissues while antagonizing its action in others. A number of structurally related SERMs are currently in advanced clinical trials. On the whole, clinical application of non-steroidal estrogens has met with limited success. Only five ER ligands are currently approved for clinical use, while several SERM-type compounds are still in advanced clinical trials (osteoporosis and breast cancer). Although a variety of related non-steroidal estrogens have been subjected to clinical evaluation, most of these compounds were not successful due to ineffectiveness, lack of improvements with respect to existing therapies or occurrence of adverse side-effects (a.o. endometrial stimulation, uterine prolapse). These rather disappointing results illustrate the difficulty of developing effective estrogens with an acceptable safety profile.
In 1996 a new estrogen receptor ERb was identified. The occurrence of two receptors and their respective tissue distribution fueled the idea that the design of subtype selective estrogens could be a viable approach to dissect the positive and negative aspects associated with estrogen therapy and to increase tissue selectivity. This strategy is attracting increased attention for two main reasons: 1) a better understanding of the individual role of the different subtypes and 2) identification of therapeutic areas that have not been associated with estrogen therapy before. Notwithstanding the fact that the appreciation of subtype selective estrogens has just started, a substantial number of publications and patents have already been disclosed, signifying major progress in this direction.
[Back to top] The Nuclear Receptor Ligand-Binding Domain: A
Family-Based Structure Analysis
Simon
Folkertsma, Paula I. van Noort, Ralph F.J. Brandt, Emmanuel Bettler, Gerrit
Vriend and Jacob de Vlieg
Nuclear receptors (NRs) are ligand-dependent transcription factors that play a central role in various physiological processes. The pharmaceutical industry has great interest in this gene-family for the discovery of novel or improved drugs for treatment of, for example, cancer, infertility, or diabetes. The usage of three-dimensional coordinates of protein structures to analyse and predict interactions with ligands is an important aspect of this process. All NR ligand-binding domains have a similar fold, which allows for comparison of the structures of their three main functional sites: the ligand-binding pocket, the cofactor-binding groove, and the dimerization interface. We performed an analysis of nearly one hundred NR ligand-binding domain structures, and identified the functionally important residues. The combined knowledge about the shape of the binding sites and the residues involved in the binding is important for drug design in two ways. First, knowledge about the location of residues that interact with a ligand in all crystal structures or in certain subfamilies assists in the design and docking of drugs. Second, similarities and differences in the residue types of the most frequent ligand- and cofactor-binding residues provide insight about potential cross-reactivity of ligands or cofactors.
[Back to top] Non-Steroidal Steroid Receptor Modulators
Rogier
C. Buijsman, Pedro H.H. Hermkens, Rachel D. van Rijn, H. Thijs Stock and N.
Miranda Teerhuis
The last ten years much attention has been focused on the finding of non-steroidal ligands for steroidal nuclear receptors for reasons such as diminishing cross-reactivity to eliminate side effect profiles, changing physicochemical properties which might cause different tissue distribution profiles and altering binding modes which influence the binding of cofactors. Compounds with a selective functionality profile are referred to as selective nuclear receptor modulators (e.g., SARMs or SPRMs). In the following paragraphs nonsteroidal ligands which have full or partial agonistic activity will be described for the following receptors: PR, GR, AR, LXR and FXR.
[Back to top] Non-Steroidal Subtype Selective Estrogens
The biological effects of estrogens are thought to be mediated by two receptors referred to as ERa and ERb. In recent years significant efforts have been devoted to the design of subtype selective ligands. These ligands are valuable tools to establish the precise biological role of each of the subtypes and to develop new generations of therapeutics. The first part of this review briefly summarizes the biology behind the estrogen receptors. The second part addresses the structure-activity relationship of the subtype selective ER ligands that were reported up to now. In the third part, the current insights in the therapeutic prospects of the subtype selective estrogens will be discussed.