Molecular Scissors: From Biomaterials Implant to Tissue Remodeling - Biologically Responsive Biomaterials for Tissue Engineering - page 22

[ 69, 94 ]. Marimastat is a broad spectrum synthetic MMP inhibitor [ 63, 108 ] acting
on MMP-1, -2, -3, -7 and -9—with good oral bioavailability that was studied in
phase II and III clinical trials in many tumor types [ 40, 117 ] .
The collection of universal chemical properties that characterizes the specific
action of a ligand in the active site of a three-dimensional conformational model of
a molecule is called a pharmacophore. The properties of the active catalytic site in
an MMP are figured by the presence of hydrogen bridges, electrostatic interactions
with an alleged inhibitor or hydrophobic areas. Pharmacophore modeling by com-
putational processing becomes a universal, comprehensive and editable process.
The inhibitor-catalytic site selectivity can be adjusted by adding or omitting some
characteristics. Our group has used the LigandScout 2.0 software [ 123, 124 ] in
order to align pharmacophores with important ligand molecules, based on their
properties, in arbitrary combinations. The alignment of the two elements is realized
by pairing only, regardless of the number of aligned elements. Thus, it is required to
define a structure as marker element. In order to define the pharmacophores, from
the 21 MMP-inhibitor complexes we have chosen nine files that are crystallographi-
cally defined in PDB databank: 1eub, 1fls, 1xuc, 1xud, 1xur, 1you, 1ztq, 456c, and
830c, respectively. We have chosen these complexes with experimentally defined
affinity constants for a further usage of the pharmacophores, based on these deter-
mined complexes. The pharmacophores represent important filters regarding in sil-
ico evaluation of new MMP inhibitors. For automatic generation of MMP
pharmacophore models we have imported the selected PDB files in LigandScout
application. Due to the fact that PDB files do not include information regarding
atom hybridization status and bond type, LigandScout application uses a complex
algorithm to analyze the ligand structure in order to assign the bond type according
to molecular geometry. Thus, it is recommended a manual check for the automatic
deduction for the ligand structure. The key structure for the inhibitors CGS 27023
and WAY-151693 in the complex structure 1eub and 1fls respectively in PDB
database is the isopropyl substituent and the basic 3-pyridyl substituent. Zn
coordination is insured by the hydroxamic group while this inhibitor is part of the
sulfonamide hydroxamates inhibitor family [ 48 ] . The non-hydroxamic inhibitor
WAY-170523 in the complex 1ztq shows the replacement of the hydroxamic acid
group with a carboxylate group; the latter is not Zn chelating but the inhibitory
action is due to correct positioning of the benzofuran moiety of the P1¢ group by a
biphenyl P1¢ linker that fills the hydrophobic S1¢ tunnel [ 94 ] .
Another inhibitor, found in the 1xuc, 1xud, and 1xur complex is represented by
pyrimidine dicarboxamide [ 17 ]. This inhibitor binds deeply in the S1¢ pocket and the
pyridyl substitutions do not approach the catalytic zinc more than 5.5 Å. This inhibitor
shows a bent conformation with the pyridyl substitutions close to Leu218.
For the pyrimidinetrione-based inhibitors of MMP13 in 1you PDB file, the
aryloxyaryl ether fits in the S1 pocket while the pyrimidinetrione binds to the
active zinc in the catalytic site [ 4, 14, 33, 97 ]. The three dimensional alignment
of two inhibitors shown a score of around 77 from 100, that is remarkable for
two different inhibitors in two different crystallographic determined structures.