title: Analysis of cocaine receptor site ligand binding by three-dimensional Voronoi site modeling approach.
abstract: The Voronoi approach has been used to obtain a three-dimensional model for the binding of the cocaine analogues at the cocaine receptor site. The method has been used to determine the geometric details and the physicochemical properties of the binding regions in the receptor site. With only eight compounds in the training set, the Voronoi site model, consisting of four regions, not only fully explains the binding affinity of the input compounds but is also successful in correctly predicting another eight compounds of the test set. The phenyl substituent at the 3-position of the tropane ring of cocaine was found to be the most significant functionality relevant for activity, while moderate contribution results from the hydrophobic interactions of the tropane ring with the binding regions. Some of the problems associated with the approach are discussed, and we report a new procedure for evaluating the validity of the model obtained from our approach.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109.
authors.forename: S
authors.initials: S
authors.lastname: Srivastava
authors.forename: G M
authors.initials: GM
authors.lastname: Crippen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003042:Cocaine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D002352:Carrier Proteins; D011955:Receptors, Drug; C061445:cocaine receptor; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine