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Document Page 181 form the lower end of the tunnel. The major effect of the different residues found here is on the diameter of the exit hole in the S1' tunnel. However, there are some residues that could be targeted for hydrogenbond formation. The S2' binding cavity is a narrow cleft that can easily accommodate a peptide backbone, but with no room for a side chain. The interaction of the P2' side chain is made with the exterior surface of the enzyme. The S2' site is exposed to solvent and presents two possible interaction sites for bound inhibitors that are related by a rotation about χ1. These sites consist of residues 179–180 on one side and residues 238–240 on the other. The S3' binding cavity opens up out of the canyon and consists almost entirely of surface interactions. The side chain of P3' interacts with residues 210 and 240, which are mostly conserved tyrosine residues. Additional interactions could be formed with some of the additional residues found in the insertions after residue 242. VI. Structure-Based Design Structure-based drug design is an iterative process that starts with a lead compound, a structural model of the target, and a structure-activity relationship http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_181.html (1 of 2) [4/5/2004 5:03:56 PM]
Document Page 182 (SAR) model. The lead compound can come from compound screening, previously discovered inhibitors, or it can be based on a known substrate. The model can be obtained from x-ray crystallography, high-field nuclear magnetic resonance spectroscopy, or from homology-based model building. Inhibitor structures are developed and docked into the model of the binding site of interest, typically the active site of the enzyme. The interactions of the inhibitor-enzyme complex are evaluated and ranked. The most promising compounds are then synthesized and tested. Based on the results of the testing, additional enzyme-inhibitor structures are determined, the SAR model is updated, and the process beings again. As a model case of structure-based drug design for MMPs we will look at the design of a right-handed inhibitor based on the x-ray structures of HFC and HNC. VII. Zinc-Binding Group The design of active-site inhibitors based on the natural substrate of the collagenases has produced a variety of zinc-binding groups to anchor the inhibitor to the catalytic zinc. These group include hydroxamates, thiols, phosphorous acid derivatives (phosphinate, phosphonate, phosphoramidate), and carboxylates. The selection of a suitable zinc-binding group has been studied in depth [37–40]. The most potent zinc-binding group found for the collagenases to date is the hydroxamate. The structural comparison of hydroxamate, carboxylate, and sulfodiimine in matrilysin provided information on the contribution of the zinc ligand to the overall potency of the inhibitor [19]. The potency of the zinc-bind group can be directly related to the number of bonds in which it is involved for this instance. The hydroxamate is the perfect bidentate ligand to the zinc with both oxygens being within 2.2 Å of the zinc. The hydroxamate group also is involved in hydrogen bonds with Glu219 and the carbonyl oxygen of Ala182. The carboxylate group is also a bidentate ligand to zinc, however the oxygens are not equidistant from the zinc. The carboxylate forms only one additional hydrogen bond with Glu219 of the enzyme. The sulfodiimine bound to matrilysin is a monodentate zinc ligand and the weakest of the zinc-binding groups. The comparison of several inhibitors with both carboxylate and hydroxamate zinc-binding groups demonstrates this property in fibroblast and neutrophil collagenases as well. While the potency of inhibitors with different zinc-binding groups maps directly to the number of bonds formed by the zinc-binding group, some of the increase in potency of the hydroxamate group over charged groups most likely is a result of the decreased energetic cost of the desolvation of the neutral hydroxamate. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_182.html [4/5/2004 5:03:58 PM]
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