Page 89 - 73_03

MARIO A. GARCÍA Y COLS. AN. R. ACAD. NAC. FARM.

zinc coordination. A positive hit for one compound is considered
when at least one of its conformers is able to coordinate the zinc ion,
for one of the NMR models, taking into account the distances and
angles restrictions described above. Eleven is then the maximum of
possible positive hits for each compound. Using this procedure, we
found 59 positive hits within a maximun of 264 (24 compounds * 11
models). AutoDock predicted that all compounds were able to
coordinate the zinc atom at least in one of the eleven NMR models
and at least in one conformation, except compound 1g.

TABLE 4. Number of positive hits through the eleven NMR models resolved for
1hov in Protein Data Bank for each docked compound

Compound Number Compound Number Compound Number Compound Number
of of of of

positive positive positive positive

hits hits hits hits

1a 1 1j 3 2j 5 3j 5
3 3k 3
1b 2 1k 2 2k 2 3l 2
5 3m 1
1c 1 1l 3 2l 2 3n 3

1d 2 1m 3 2m i52 2

1e 2 1n 4 2n

1f 1

1g 0

1h 2

1i 2

MMP-2 inhibitors should not only be good zinc coordinating
agents, but also they should interact with key amino acids which are
crucial for the ligand binding (7, 33, 34). Taking into account this
information, the 98 positive docking hits were visually inspected
displaying the residues within 4 Å around the ligand. Thus, residues
belonging to S1, S2, S3, S1’, S2’, and S3’ subsites were analyzed
looking for putative interactions with each of the 98 conformers
(data not shown). Compound i52 was included in this analysis
to provide a reference for contacts with the residues belonging to
the different subsites. Interactions with S1’ residues were used as
a filter to select 27 docking conformers, belonging to 15 different

718