title: Towards a rational spacer design for bivalent inhibition of estrogen receptor.
abstract: Estrogen receptors are known drug targets that have been linked to several kinds of cancer. The structure of the estrogen receptor ligand binding domain is available and reveals a homodimeric layout. In order to improve the binding affinity of known estrogen receptor inhibitors, bivalent compounds have been developed that consist of two individual ligands linked by flexible tethers serving as spacers. So far, binding affinities of the bivalent compounds do not surpass their monovalent counterparts. In this article, we focus our attention on the molecular spacers that are used to connect the individual ligands to form bivalent compounds, and describe their thermodynamic contribution during the ligand binding process. We use computational methods to predict structural and entropic parameters of different spacer structures. We find that flexible spacers introduce a number of effects that may interfere with ligand binding and possibly can be connected to the low binding affinities that have been reported in binding assays. Based on these findings, we try to provide guidelines for the design of novel molecular spacers.
authors.affiliation: Zuse Institute Berlin, Takustraße 7, 14195 Berlin, Germany. bujotzek@zib.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Bujotzek
authors.forename: Min
authors.initials: M
authors.lastname: Shan
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.forename: Marcus
authors.initials: M
authors.lastname: Weber
mesh_terms: D001665:Binding Sites; D017605:Bromine Compounds / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D019277:Entropy; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017605:Bromine Compounds; D008024:Ligands; D011960:Receptors, Estrogen