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side) inhibitors will bind with greater affinity. Indeed, most of the structures of MMPs were determined
with right-hand side inhibitors, and most of the pharmaceuticals currently in development are also righthand
side binders. A closer look at the binding pockets themselves also demonstrates the reasons for the
preference of researchers for the right-hand side.
V. Substrate-Binding Pockets
The nonprimed or left-hand side of the cleft consists of a large shallow depression. The S1 pocket
consists of a shallow ridge that complements the glycine residue of the collagen strands. Most of the
interactions with the glycine residue are brought about due to its interaction with the catalytic zinc.
Asparagine 180 approaches the P1 residue in HFC. Crystallographic evidence indicates an interaction of
the thiophene ring of batimastat via electrostatic interactions of the p orbitals and the catalytic zinc and
the possibility of a water-mediated hydrogen bond to the carbonyl O of residue 184 [35]. Larger
substituents can be accommodated in regions adjacent to the P1 pocket, possibly in the large pocket
above the S1 site (see Figure 2). Increased potency was noted for several compounds with cyclic imido
P1 substituents that could bind here [2].
The S2 pocket is a large shallow depression offering no real binding cavities. One side of the pocket is
made up from the conserved histidine at position 228 and the main chain from residue 227. The bottom
of the pocket is formed by histidine 222. Both of these histidines are liganded to the catalytic zinc. The
other side consists mostly of the residue 186 side chain with some hydrogen-bonding contacts possible
from the tip of the glutamine side chain in the case of HFC and HNC.
The S3 pocket offers a shallow cavity to bind the conserved proline. The proline residue of the substrate
would lie between the side chains of His 183, Phe 185, and Ser172 [36]. Residues 183 and 185 are
conserved among the MMPs with the minor exception of a tyrosine replacing phenylalanine 164 in
stromelysin. Residue 172 shows some variability among the MMPs existing as a serine in HNC and
HFC and a tyrosine in the remainder of the aligned MMPs.
The primed or right-hand side of the active site exists as a narrow canyon with a large well at the
beginning. The S1' pocket is a narrow, deep cavity providing an ideal binding site for inhibitor design.
The S1' pocket is the most significant feature of the surface, extending as a tunnel completely through
the enzyme in the case of neutrophil collagenase and stromelysin. This feature makes the S1' pocket an
ideal candidate for use in designing an inhibitor with specificity for HNC, HFC, or HFS.
The volumes of the S1' pockets vary greatly. Matrilysin has the smallest S1' pocket at 111 Å 3. The
fibroblast collagenase pocket is not much larger at
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