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Title: Using a Biochemical Pathways Database for Deriving Transition-State Drug Analogs | P131 |
Reitz, Martin; Sacher, Oliver; Gasteiger ,Johann martin.reitz@chemie.uni-erlangen.de, sacher@mol-net.de Universität Erlangen |
| Biochemical reaction pathways represent a complicated network and gain increasing interest in modern drug research. The goal of our project is a better understanding of those processes on their chemical behavior. For this reason a database of biochemical reactions was developed at the Computer-Chemie-Centrum within a cooperative project. The basis of this database are the posters "Biochemical Pathways" of Boehringer Mannheim [1, 2]. In contrast to other related projects, in this database all reactions are stored with the exact stoichiometric information, all reaction centers are marked and all atoms are tagged by atom-atom-mapping. Therefore, this database provides a powerful tool for the investigation of biochemical structures, reactions and reaction pathways on their mechanistic base. For the textual and structural retrieval from those databases the C@ROL program system was developed by Molecular Networks, providing fast and efficient search algorithms, like 3D substructure searches. In our investigation we used the biochemical database as a starting point for deriving transition-state drug analogs. We selected the AMP-Deaminase from the database, an enzyme which provides a relevant function in purine nucleotide metabolism. This enzyme was well examined in recent years and there are efficient transition state analogs known. Because the three-dimensional structure of a ligand is crucial for the optimal binding at the enzyme binding-site, those molecules are strong inhibitors of enzyme function and give prospect on high specific and effective drugs. Therefore, it is important to recognize such transition state analogs and to extract them from a compound database. For this purpose we developed the program system GAMMA [3] which superimposes the three-dimensional structure of molecules using genetic algorithms in order to determine structural similarities. The generation of three-dimensional structures was performed by CORINA [4]. Thus we can show that the transition-state of AMP-Deaminase and its analog drug coformycin [5] show striking similarity in their three-dimensional structure, despite having structural differences in their two-dimensional structures. |
| [1] G. Michal (Ed.), Biochemical Pathways (Poster), Boehringer Mannheim, Penzberg 1993. [2] G. Michal (Ed.), Biochemical Pathways. Wiley, New York 1999. [3] S. Handschuh, J. Gasteiger, J. Mol. Model 2000, 6, 358. [4] J. Sadowski, J. Gasteiger, Chem. Reviews 1993, 93, 2567. [5] C. B. Bookser, R. K. Srinivas et al., J. Med. Chem. 2000, 43, 1495. |