title: CoMSIA and docking study of rhenium based estrogen receptor ligand analogs.
abstract: OPLS all atom force field parameters were developed in order to model a diverse set of novel rhenium based estrogen receptor ligands whose relative binding affinities (RBA) to the estrogen receptor alpha isoform (ERalpha) with respect to 17beta-estradiol were available. The binding properties of these novel rhenium based organometallic complexes were studied with a combination of Comparative Molecular Similarity Indices Analysis (CoMSIA) and docking. A total of 29 estrogen receptor ligands consisting of 11 rhenium complexes and 18 organic ligands were docked inside the ligand-binding domain (LBD) of ERalpha utilizing the program Gold. The top ranked pose was used to construct CoMSIA models from a training set of 22 of the estrogen receptor ligands which were selected at random. In addition scoring functions from the docking runs and the polar volume (PV) were also studied to investigate their ability to predict RBA ERalpha. A partial least-squares analysis consisting of the CoMSIA steric, electrostatic and hydrophobic indices together with the polar volume proved sufficiently predictive having a correlation coefficient, r(2), of 0.94 and a cross-validated correlation coefficient, q(2), utilizing the leave-one-out method of 0.68. Analysis of the scoring functions from Gold showed particularly poor correlation to RBA ERalpha which did not improve when the rhenium complexes were extracted to leave the organic ligands. The combined CoMSIA and polar volume model ranked correctly the ligands in order of increasing RBA ERalpha, illustrating the utility of this method as a prescreening tool in the development of novel rhenium based estrogen receptor ligands.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63110, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wolohan
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004958:Estradiol / Q000031:analogs & derivatives; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000737:chemistry*; D004968:Estrogens, Non-Steroidal / Q000737:chemistry; D021621:Imaging, Three-Dimensional; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000819:agonists* / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D012984:Software; D013816:Thermodynamics
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D008024:Ligands; D009942:Organometallic Compounds; D011720:Pyrazoles; D011960:Receptors, Estrogen; D004958:Estradiol; D012211:Rhenium