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Document Figure 15 The energy profiles and MEP surfaces (–20 kcal/mol) for catechol (black) and 3,5-dinitrocatechol (grey). decreases the activating negative potential substantially. As a consequence, the OH group is weakly nucleophilic and 3,5-dinitrocatechol is not a substrate of COMT but a potent inhibitor. VII. Inhibitor Design Page 358 The drug-design process of COMT inhibitors started long before the structure of the target molecule was available. The most important results were extracted from the QSAR studies of substituted catechols [26,42]. Those investigations clearly indicated the importance of the acidity of one of the two hydroxyl groups in the catechol ring. The ionization of the hydroxyl was greatly influenced by electronwithdrawing substituents in the positions ortho and para to the hydroxyl. The lipophilicity of the side chain was predicted, but after the determination of the enzyme structure it became clear that the active site of COMT is a relatively shallow groove where ligands with longer side chains http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_358.html [4/5/2004 5:29:56 PM]
Document Page 359 easily reach the surface of the enzyme. The pharmacophore model constructed with biochemical and QSAR knowledge [42] was surprisingly good and realistic in comparison to the experimental structure. The crucial role of the magnesium ion for the binding of substrates and catalysis was not given enough attention. Even without the experimental knowledge of the three-dimensional structure of COMT, the correct decision for the direction of the drug-design process was possible. Many open questions were still waiting for the determination of the molecular structure. The most important drug-design aspects under consideration included the optimization of the pharmacokinetic properties of the molecules, especially the penetration across the blood brain barrier. The structure of COMT clearly showed that with catechol-type inhibitors, one of the positions ortho to the hydroxyls is optimally substituted by a nitro group, while the other ortho position has to be unsubstituted. Sterically, the two remaining sites can be substituted quite freely, so that these substitution positions can be used to modify the physicochemical properties of the inhibitors. The question of the possibility of designing an inhibitor without the catechol structure is important, because the potent inhibitors which rely on the ionization of a catechol hydroxyl, penetrate very poorly into the brain. In clinical trials of the therapeutic use of COMT inhibitors it has become evident that the beneficial effect to L- dopa metabolism is fully reached with peripheral inhibitors such as entacapone [27–29]. As demonstrated above, based on the threedimensional structure of COMT, the design of potent noncatechol type inhibitors may be very tedious. The active site of COMT is a rather simple environment with a few catalytic residues and a magnesium ion defining the structural limits of the catechol ligands. VIII. Clinical Possibilities of Inhibitors of COMT A. Parkinson's Disease Parkinson's disease is a neurological disorder that affects voluntary movement. The symptoms are slowness of movement, rigidity, and tremor. The reason for the disease is unknown. Parkinson's disease is a progressive disorder and involves the deterioration of dopaminergic nerve fibers in substantia nigra, which leads to a striatal deficiency of dopamine. The symptoms of Parkinson's disease are detected only after about 80% of the dopamine-producing neurons are degenerated. There is no known cure but the symptoms are treated with a combination of different drugs. Current and Future Therapy of Parkinson's Disease Dopamine does not penetrate the blood-brain barrier. L-Dopa is actively transported into the brain and then converted to dopamine. L-Dopa is rapidly metabolized and only about 1% of an oral dose reaches the brain. In the current http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_359.html [4/5/2004 5:30:04 PM]
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Structure-based Drug Design 14 Stru
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Page 415 and 416: Document 17. Szelke M. Chemistry of
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Document Page 476 nM, respectively.
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Document A. The Canyon Page 491 The
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Document Subsequent studies have sh
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Document Page 495 of the RNA and pr
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Document Figure 4 A ribbon diagram
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Document Med Biol 1991; 306:9-21; (
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document antagonistic activity, 416
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Document Kininogen, 119 high molecu
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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