Background to the study
Drug discovery utilizes various bioactive molecules, which according to Mocklinghoff et al. (2005), have scaffold structures. As a result, these scaffold structures form the basis of studies aimed at determining the molecular diversity, structural complexity, structure-based molecular optimization, and structure-activity relationships (SAR) of the bioactive molecules. In some cases, a library of scaffolds can be organized to form tree-like arrays, which aid scientists to identify novel ligands of bioactive molecules. Furthermore, the arm-like structures derived from the scaffolds can range from complex to simple structures, which are used to construct newer analogs of known bioactive molecules that enable scientists to study their structural/molecular diversity and their receptor binding properties (Mocklinghoff et al. 2005).
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Using the same approach, scientists have identified new fragments (Tetrahydroisoquinoline-THIQ derivatives) derived from complex scaffolds that show affinity and selectivity for the estrogen-receptor (ER). Subsequently, by focusing on a small library of the THIQ fragments, researchers have achieved the optimization of the binding mechanism and the SAR of a small bicyclic THIQ, which shows affinity and selectivity for the Beta-ER. Consequently, the discovery of this new fragment offers many scientists the opportunity to study the SAR and receptor selectivity of the THIQ derivatives, and therefore, chances are that newer selective ligands for the estrogen-receptor (ER) will be developed in the near future (Mocklinghoff et al. 2006).
The report aims at providing a complete summary of the article, “Design and Evaluation of Fragment-Like Estrogen Receptor Tetrahydroisoquinoline Ligands from a Scaffold-Detection Approach.”
The report entails a summary of the experimental design and synthesis of the THIQ derivatives, the biochemical evaluation of the THIQ fragments, and the structural evaluation of the THIQ fragments as described in the article.
Design and Synthesis
In this article, the researchers designed a small library of THIQ scaffolds consisting of 18 fragments (Mocklinghoff et al. 2006). Subsequently, the fragments were studied relative to their structural diversity and affinity for the alpha-and beta-estrogen receptors. Accordingly, the researchers noted that the structure of THIQ consists of a bicyclic-ring system that is almost similar to the A-and B-rings of the endogenous ligand of the ER known as 17-Beta-estradiol (E2). Thus, THIQ fragments with ER affinity were synthesized by introducing –OH groups at various locations on the THIQ aromatic ring. Further, through N-substitution, small side-chains were introduced to the THIQ scaffolds to increase their ER affinity and selectivity (Mocklinghoff et al. 2006). Lastly, the electron-withdrawing ability of some functional groups such as the amides was also examined at different positions of the aromatic ring.
Here, the assay entails the binding of fluorescein-labeled probes with the ligand-binding domains (LBDs) of the estrogen receptor, which is already bound by the THIQ ligands. As a result, the labeled agonistic probes will bind to the LBDs thus increasing polarization. Conversely, antagonistic probes will repress the ability of the LBDs to bind the probes, and thus, polarization is decreased (Mocklinghoff et al. 2007). Consequently, the researchers discovered that out of the 18 designed THIQ fragments, 11 fragments showed an increased affinity for the ER-LBDs, and therefore, they are said to induce the interaction between the probes and the ER-LBDs. Furthermore, the study shows that –OH groups in the THIQ ring do not facilitate ER binding or recognition by themselves (Mocklinghoff et al. 2007-2008).
This assay utilizes the X-ray crystal structures of the Beta-ER-LBD complexes to determine the ER affinity and selectivity of the THIQ fragments. Here, the researchers designed crystal structures consisting of Beta-ER-LBDs, 17-Beta-Estradiol (E2), and three THIQ fragments. These structures were then complexed with the steroid receptor coactivator-1 (SRC-1). Subsequently, a comparison of these complexes with other structures like the E2-bound estrogen receptor alpha with relevant agonists shows that their structures are similar. Moreover, the researchers noted that all the three THIQ fragment complexes consist of the 12-helix conformation, which is similar to the 12-helix conformation in the structure of the E2-bound estrogen receptor beta with relevant agonists (Mocklinghoff et al. 2007-2009).
This report provides a summary of an article describing the use of a library of scaffolds in the discovery of novel molecules. Here, it is certain that drug discovery entails the process of arranging scaffolds into tree-like arrays, which can provide insights into the structural diversity and the binding mechanisms of bioactive molecules. As a result, the article summarized in this report describes a process that utilizes the tree-like arrays of known scaffolds to identify a small bicyclic THIQ fragment, which shows Beta-ER affinity and selectivity. Therefore, this study forms the basis through which future scientists can discover novel bioactive molecules showing specific properties for the estrogen receptors.
Mocklinghoff, Sabine et al. “Design and evaluation of fragment-like estrogen receptor Tetrahydroisoquinoline ligands from a scaffold-detection approach.” Journal of Medicinal Chemistry, 54(2011): 2005-2011. Print.