title: Structural studies of several clinically important oncology drugs in complex with human serum albumin.
abstract: BACKGROUND
  Serum albumin is a major pharmacokinetic effector of drugs. To gain further insight into albumin binding chemistry, the crystal structures of six oncology agents were determined in complex with human serum albumin at resolutions of 2.8 to 2.0Å: camptothecin, 9-amino-camptothecin, etoposide, teniposide, bicalutamide and idarubicin.
  
  
  METHODS
  Protein crystal growth and low temperature X-ray crystallography
  
  
  RESULTS
  These large, complex drugs are all bound within the subdomain IB binding region which can be described as a hydrophobic groove formed by α-helices h7, h8 and h9 covered by the extended polypeptide L1. L1 creates a binding cavity with two access sites, one between loop L1 and α-helices h7 and h8 (distal site: IBd) and the other between L1 and α-helix h9 (proximal site: IBp). Camptothecin (2.4Å) and 9 amino camptothecin (2.0Å) are clearly bound as the open lactone form (IBp). Idarubicin (2.8Å) binds in a DNA like dimer complex via an intermolecular π stacking arrangement in IBd. Bicalutamide (2.4Å) is bound in a folded intramolecular π stacking arrangement between two aromatic rings in IBd similar to idarubicin. Teniposide (2.7Å) and etoposide (2.7Å), despite small chemical differences, are bound in two distinctly different sites at or near IB. Teniposide is internalized via primarily hydrophobic interactions and spans through both openings (IBp-d). Etoposide is bound between the exterior of IB and IIA and exhibits an extensive hydrogen bonding network.
  
  
  CONCLUSIONS
  Subdomain IB is a major binding site for complex heterocyclic molecules.
  
  
  CONCLUSIONS
  The structures have important implications for drug design and development. This article is part of a Special Issue entitled Serum Albumin.
authors.affiliation: New Century Pharmaceuticals, Inc., 895 Martin Road, Suite C, Huntsville, AL 35824, USA.
authors.forename: Zhong-min
authors.initials: ZM
authors.lastname: Wang
authors.forename: Joseph X
authors.initials: JX
authors.lastname: Ho
authors.forename: John R
authors.initials: JR
authors.lastname: Ruble
authors.forename: John
authors.initials: J
authors.lastname: Rose
authors.forename: Florian
authors.initials: F
authors.lastname: Rüker
authors.forename: Melanie
authors.initials: M
authors.lastname: Ellenburg
authors.forename: Robert
authors.initials: R
authors.lastname: Murphy
authors.forename: James
authors.initials: J
authors.lastname: Click
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Soistman
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilkerson
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Carter
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D012709:Serum Albumin
keywords: Anticancer drug; Drug design; Human serum albumin; Oncology; Structure; Subdomain IB