A model for the dopamine D₄pharmacophore

Abstract

The aim of this work has been to design specific regulators of glycogen phosphorylase (GP) that shift the balance from glycogen degradation to glycogen synthesis. Such compounds have potential therapeutic interest in the treatment of non-insulin dependent (Type II) diabetes mellitus (NIDDM). Several compounds have been designed based on the three-dimensional rabbit muscle GP structure (Watson et al.. Biochemistrv 1994. 33. 5745-5758). Analysis of the crystallographically refined. complexes has offered some understanding of the factors influencing sugarprotein interactions. To date, the best inhibitor. a glucopyranose analogue of hydantocidin, shows a I 000 fold improvement over the parent glucose moiety (Bichard et al..Tetrahed. Lett. 1995, 36, 2145-2148. It has been shown, with an earlier analogue (showing two orders of magnitude improvement over glucose) that the compound is an effective regulator of liver glycogen metabolism and is considerably more effective than glucose (Board & Johnson, Bioclzem. J. 1995, 311, 845-852). The results indicate a positive hypoglyceaemic effect and suggest q potential use for these analogues in the treatment of Type II diabetes.Both structure-based and quantitative structure-activity relationship (QSAR) drug design strategies have been used (Watson et al., Acta Crystallog1: 1995, D5 L 458-472). The additional information from the QSAR approach provides a quantitative method for the design and prediction of new potential drug molecules. We have used the program combination GRID (Wade & Goodford, J. lvfed. Chenz. 1993, 36, 140) and GOLPE (Baroni et al., Quant. Struct.-Act. Rei at. 1993, 12, 9-20). The latest version of GOLPE (V3.0) has been adapted to use structural information of both the ligand and the protein molecules (traditional methods focus only on the ligand). To date, there is no QSAR methodology that simultaneously uses the inhibitor-macromolecular complex structures and biological data to predict the activity of new drug molecules. Our GP dataset, together with the latest program GOLPE, have provided a unique opportunity to explore such an approach.MS05.01.06 RELIBase -AN OBJECT-ORIENTED COM-PREHENSIVE RECEPTOR-LIGAND DATABASE. M. Hendlich, F. Rippmann, G. Bamickel, Preclinical Research, Merck KGaA, 6427 L Darmstadt Gerr:nany, K. Hemm, K. Aberer, GMD-IPSI, 64293 Darmstadt, Germany New biomolecular and computational methods have led to an explosion in the available data about receptor/ligand complexes. Unfortunately, existing data is spread over different databases or is not available in electronic format at all. Therefore, we have developed a comprehensive database system for receptor/ligand complexes which combines crystallographic information from the Brookhaven Protein Databank (PDB) with biomolecular information like sequence alignments and infom1ation about mutations from various other data sources. RELIBase allows complex queries (including substructure searches, similarity searches and searches for specific interactions) regarding both small molecule and ...