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to develop an appropriate SAR is demonstrated in the case of the inhibitors shown in Table 1. The
unusual potency of a benzylic ether for HFC was unexpected and would not have been predicted with
standard docking and minimization studies (Figure 6).
Page 186
The differences in the potency of the various 4-substituted analogs of inhibitor 10 against HFC suggest ππ
interactions are the driving force for the displacement of arginine 214. The electron-withdrawing Cl
substitution decreases the affinity for HFC while increasing the affinity for HFS. The leading 4-pentyl
group can not effectively interact with arginine 214 in HFC; therefore, the rearrangement does not
occur. The open channel that is present in HFS and gelatinase B presents no such impediment to binding
and the affinity is essentially equal to the unsubstituted form.
Not all structure-based design experiments are successful. Attempts to displace the arginine residue that
caps the S1' pocket of HFC by forming a salt link with a P1' carboxylate or hydroxyl moiety were
unsuccessful [42]. However, these failed attempts offer some redeeming features in the refinement of
parameters that can be used to evaluate the energetic potentials for displacing buried water molecules as
well as the inherent desolvation energies for polar compounds.
The outlook for structure-based drug design is good. The advancement in both x-ray area detectors and
computer hardware will make the determination of a series of compounds bound to a target enzyme for
use in SAR development commonplace in drug-discovery efforts. The continued explosion of structural
studies will lead to an increased understanding of the dynamics of protein interactions, which will, in
turn, lead to better docking algorithms. The combination of structural information and greater
computational power will also make more accurate predictions of protein—ligand interactions possible.
References
1. Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler
JA. Matrix metalloproteinases: a review. Crit. Rev. Oral. Biol. Med. 1993; 4:197–250.
2. Beckett RP, Davidson AH, Drummond AH, Huxley P, Whittaker M. Recent advances in matrix
metalloproteinase inhibitor research. DDT 1996; 1:16–26.
3. Birkdell-Hansen H. Proteolytic remodeling of extracellular matrix. Cur. Op. Cell Biology 1995;
7:728–735.
4. Stocker W, Grams F, Baumann U, Gomis-Ruth F-X, McKay DB, Bode W. The metzincins
topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins
(collagenases) define a superfamily of zinc peptidases. Protein Sci. 1995; 4:823–840.
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