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Document VIII. S1' Interactions Matrix metalloproteinase structural studies of the P'-side inhibitors to date show a common set of inhibitor-enzyme interactions. This can be attributed primarily to the strong directional zinc-binding forces. Further stabilizing forces from the backbone hydrogen-bonding patterns common to a β sheet allow for minor adjustments due to the zinc interactions to be made while maintaining a common pharmacophore. Page 183 The fairly rigid constraints of binding based on the known hydroxamate inhibitors allows the use of computer-aided modeling to play a useful role in the design of specific MMP inhibitors. Exploration of the S1' pocket was carried out by docking the P1' group within the cavity followed by rounds of energy minimization. In order to maintain the integrity of the MMP structure several limitations were used. All MMP atoms that are greater than 8 Å from the docked inhibitor were frozen. The Cα atoms of all residues within 8 Å of the inhibitor were initially constrained to their original position by a 20 kcal/mol Å 2 force constant that was gradually relaxed to 1 kcal/mol Å 2. Strong initial constraints were also placed on the conserved hydrogen bonds and zinc-ligand interactions. This method has several advantages and disadvantages over the common static treatment of target structures. The advantages are that it more closely approximates the actual dynamic state of protein structure and is not computationally prohibitive. The disadvantages include the increased computational cost over a static enzyme target and the fact that gross structural rearrangements can still not be accounted for. The structural similarity of the active site of the MMP family allows structure-based drug design to effectively be used for those enyzmes whose structures have not been determined yet. Examination of the S1' cavities of HFC and HNC clearly indicates a path for designing inhibitors that bind preferentially (Figure 5). The cavity of HFC is mostly filled by the leucine side chain of the preferred substrate, while the S1' pocket of HNC [26] and HFS [30] remains unfilled. The sequence similarities of the gelatinases with HNC indicate that they too can accommodate a much larger P1' group. A series of compounds was designed to explore filling the long S1' tunnel of gelatinase B [41, 42]. The optimum length for binding to gelatinase B was found. There was an increase in affinity for the phenolic ethers versus the benzylic ethers of the same overall length for binding to gelatinase B, but there was no preference seen in binding to HFS. Surprisingly the phenolic ethers also showed potent binding to HFC. The size of the bottom of the S1' pocket and the differences in the preferred torsion angle for the bond to the aromatic ring both play a role in this differential binding. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_183.html [4/5/2004 5:03:59 PM]
Document IX. S2' Interactions Page 184 The interactions at the S2' site display an interesting structure-activity relationship. While the interactions do not include any hydrogen bonds, favorable stacking interactions do play a significant role in binding. A glycine residue at P2' results in a loss of three orders of magnitude in potency for otherwise identical inhibitors [41]. There is a preference for an aromatic ring at this position in natural peptide substrates [43]. Structural considerations also allow the placement of a t-butyl group here. The potency of a t-butyl glycine P2' is less than that of a phenylalanine (Table 1), but the expected gain in bioavailability brought about by shielding the amide bond from solvation effects should compensate for the loss in potency. X. Conclusions High resolution x-ray crystallographic structure determination is an essential step in structure-based drug design. The need for high resolution structural data http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_184.html [4/5/2004 5:04:31 PM]
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