title: Application of screening methods, shape signatures and engineered biosensors in early drug discovery process.
abstract: OBJECTIVE
  In this study, two unreported estrogen antagonists were identified using a combination of computational screening and a simple bacterial estrogen sensor.
  
  
  METHODS
  Molecules here presented were initially part of a group obtained from a library of over a half million chemical compounds, using the Shape Signatures method. The structures within this group were then clustered and compared to known antagonists based on their physico-chemical parameters, and possible binding modes of the compounds to the Estrogen Receptor alpha (ER alpha) were analyzed. Finally, thirteen candidate compounds were purchased, and two of them were shown to behave as potential subtype-selective estrogen antagonists using a set of bacterial estrogen biosensors, which included sensors for ER alpha, ER beta, and a negative control thyroid hormone beta biosensor. These activities were then analyzed using an ELISA assay against activated ER alpha in human MCF-7 cell extract.
  
  
  RESULTS
  Two new estrogen receptor antagonists were detected using in silico Shape Signatures method with an engineered subtype-selective bacterial estrogen biosensor and commercially available ELISA assay. Additional thyroid biosensor control experiments confirmed no compounds interacted with human thyroid receptor beta.
  
  
  CONCLUSIONS
  This work demonstrates an effective combination of computational analysis and simple bacterial screens for rapid identification of potential hormone-like therapeutics.
authors.affiliation: Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, 600 S. 43rd Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Hartman
authors.forename: Alison R
authors.initials: AR
authors.lastname: Gillies
authors.forename: Sonia
authors.initials: S
authors.lastname: Arora
authors.forename: Christina
authors.initials: C
authors.lastname: Andaya
authors.forename: Nitya
authors.initials: N
authors.lastname: Royapet
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: David W
authors.initials: DW
authors.lastname: Wood
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Zauhar
mesh_terms: D015374:Biosensing Techniques / Q000379:methods*; D002616:Chemical Engineering / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D004965:Estrogen Antagonists / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D006801:Humans; D013997:Time Factors
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha