title: Quantitative structure-activity relationship modeling of dopamine D(1) antagonists using comparative molecular field analysis, genetic algorithms-partial least-squares, and K nearest neighbor methods.
abstract: Several quantitative structure-activity relationship (QSAR) methods were applied to 29 chemically diverse D(1) dopamine antagonists. In addition to conventional 3D comparative molecular field analysis (CoMFA), cross-validated R(2) guided region selection (q(2)-GRS) CoMFA (see ref 1) was employed, as were two novel variable selection QSAR methods recently developed in one of our laboratories. These latter methods included genetic algorithm-partial least squares (GA-PLS) and K nearest neighbor (KNN) procedures (see refs 2-4), which utilize 2D topological descriptors of chemical structures. Each QSAR approach resulted in a highly predictive model, with cross-validated R(2) (q(2)) values of 0.57 for CoMFA, 0.54 for q(2)-GRS, 0.73 for GA-PLS, and 0.79 for KNN. The success of all of the QSAR methods indicates the presence of an intrinsic structure-activity relationship in this group of compounds and affords more robust design and prediction of biological activities of novel D(1) ligands.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: B
authors.initials: B
authors.lastname: Hoffman
authors.forename: S J
authors.initials: SJ
authors.lastname: Cho
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.forename: S
authors.initials: S
authors.lastname: Wyrick
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
authors.forename: R B
authors.initials: RB
authors.lastname: Mailman
authors.forename: A
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D000465:Algorithms; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000737:chemistry* / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; D008024:Ligands; D017447:Receptors, Dopamine D1