ANALYSIS OF COCAINE RECEPTOR-SITE LIGAND-BINDING BY 3-DIMENSIONAL VORONOI SITE MODELING APPROACH

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 mode l, consisting of four regions, not only fully explains the binding aff inity of the input compounds but is also successful in correctly predi cting 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 m ost significant functionality relevant for activity, while moderate co ntribution results from the hydrophobic interactions of the tropane ri ng with the binding regions. Some of the problems associated with the approach are discussed, and we report a new procedure for evaluating t he validity of the model obtained from our approach.