Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC.

A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetical binding site cavity. The model not only consists of the geometry of the binding cavity but also gives the weight of the various physicochemical properties of the ligands at different parts of the binding cavity responsible for their binding to the receptor. The model fitted the binding data with a correlation coefficient of 0.980, a SD of 0.223, and an explained variance of 0.898. It suggested that a small hydrophilic group is favored at position 1 of the benzodiazepine ring, the C = O region of this ring is favored by dispersive atoms and positive charge, the 4'-substituent of the 5-phenyl group is subject to strong steric repulsion, the 7- position is favored to be a hydrophilic group, and the 8- and 9- positions and their substituents are favored to be dispersive as well as hydrophilic groups. It also suggested that the substitution of the 5-phenyl group by the more dispersive 2-thiophene may increase the binding affinity. The model was allowed to predict the binding affinity data of five compounds with extensive variation of the structure from the training set; the prediction for four compounds was excellent. Some of the problems of the method have been discussed with their possible remedies.