ACS Medicinal Chemistry Letters
Letter
contribution. These findings suggest that the QM ΔΔGsolv
could be considered as an additional parameter in the
evaluation of docking results when structurally related
compound are analyzed before the synthetic approach.
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In summary, by applying an integrating structure-based
approach, a new scaffold for potent MMP inhibitors has been
designed. All the related compounds here synthesized and
studied by X-ray crystallography and fluorimetric assays show a
high affinity toward MMP-12 and a significant selectivity with
respect to MMP-1 and MMP-7. Binding modes to MMP-12
predicted by docking were confirmed by X-ray crystallographic
data. Computational results indicate that the ethylene linker
may contribute to the binding affinity by establishing new van
der Waals interactions with the S1′ pocket of the protein.
Conversely, ab initio PCM calculations show that the
introduction of the D-proline ZBG determines a significant
increase of theoretical free energy of solvation for these
compounds, which might contribute significantly to the
observed high affinity. It is worth noting that the predicted
water solubility of compounds bearing the D-proline moiety is
still highly compatible with the ideal tolerance limits described
for hit and lead compounds.14,31 The contribution of the
investigated chemical modifications to the arylsulfonamide
scaffold allows the use of ZBGs different from the hydroxamic
acid. Notably, 7* is endowed with a strong inhibitory activity
toward MMP-12 and characterized by the carboxylic acid ZBG,
which is generally associated with a lower affinity for zinc than
hydroxamic acid,25,27 but with a safer toxicity profile. This
compound could be a valuable tool in investigating the biology
of MMP-12 catalytic activity and might be a promising lead
molecule for the development of medicinally active agents.
ASSOCIATED CONTENT
* Supporting Information
■
S
Chemistry directions, crystallographic data of PDB IDs 3RST,
3RTT and 4GUY, chemical structures, logP values, fluorimetric
assays, QM data, docking analysis, binding mode of 7*, single
atom enthalpy contribution, and correlation between exper-
imental and docking data. This material is available free of
AUTHOR INFORMATION
Corresponding Author
■
Present Address
†M.M.: IITIstituto Italiano di TecnologiaCenter for Life
Nano Science IIT@Sapienza, Viale Regina Elena 295, Roma,
Italy.
Author Contributions
‡M.M. and A.M. contributed equally.
Funding
This work was supported by the EC (Projects: SFMET No.
201640, INSTRUCT No. 211252, and Bio-NMR No. 261863),
by MIUR (Prot. RBLA032ZM7 and Prot. RBIP06LSS2), and
by Ente Cassa di Risparmio di Firenze.
(15) Bertini, I.; Calderone, V.; Fragai, M.; Giachetti, A.; Loconte, M.;
Luchinat, C.; Maletta, M.; Nativi, C.; Yeo, K. J. Exploring the subtleties
of drug-receptor interactions: The case of matrix metalloproteinases. J.
Am. Chem. Soc. 2007, 129 (9), 2466−2475.
(16) Attia, M. I.; Timmermann, M.; Hogger, P.; Herdeis, C. Design,
synthesis and biological activity of azasugar-based CD163 ectodomain
shedding inhibitors. Eur. J. Org. Chem. 2007, 22, 3669−3675.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors want to thank Professor Kenneth M. Merz, Jr., for
the helpful discussions on ab initio calculations.
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dx.doi.org/10.1021/ml300446a | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX