La Pietra, Valeria
(2010)
Identification of novel molecular scaffolds for the design of MMP-13 inhibitors through Virtual Screening Methods.
[Tesi di dottorato]
(Unpublished)
| Item Type: |
Tesi di dottorato
|
| Resource language: |
English |
| Title: |
Identification of novel molecular scaffolds for the design of MMP-13 inhibitors through Virtual Screening Methods |
| Creators: |
| Creators | Email |
|---|
| La Pietra, Valeria | valeria_lapietra@hotmail.com |
|
| Date: |
30 November 2010 |
| Number of Pages: |
58 |
| Institution: |
Università degli Studi di Napoli Federico II |
| Department: |
Chimica farmaceutica e tossicologica |
| Scuola di dottorato: |
Scienze farmaceutiche |
| Dottorato: |
Scienza del farmaco |
| Ciclo di dottorato: |
23 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| D'Auria, Maria Valeria | UNSPECIFIED |
|
| Tutor: |
| nome | email |
|---|
| Marinelli, Luciana | lmarinel@unina.it |
|
| Date: |
30 November 2010 |
| Number of Pages: |
58 |
| Keywords: |
MMP-13, inhibitors, Osteoartrite |
| Settori scientifico-disciplinari del MIUR: |
Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica |
[error in script]
[error in script]
| Date Deposited: |
14 Dec 2010 10:19 |
| Last Modified: |
30 Apr 2014 19:46 |
| URI: |
http://www.fedoa.unina.it/id/eprint/8428 |
| DOI: |
10.6092/UNINA/FEDOA/8428 |
Collection description
Osteoarthritis (OA) is the leading cause of joint pain and disability in
middle-aged and elderly patients. It is characterized by progressive loss of
articular cartilage that eventually leads to denudation of the joint surface.
The cartilage loss observed in OA is the result of a complex process
involving degradation of various components of the cartilage matrix.
Particularly, degradation of cartilage-specific type II collagen by
mammalian collagenases (MMPs) is a key step in the loss of structural and
functional integrity of cartilage.1 Among all known MMPs, MMP-13 is
considered the principal target in OA. Indeed, today there are
overwhelming data on the role of MMP-13 in the pathogenesis of OA,2 and
inhibition of its activity has proven to be efficacious in a variety of models
of experimentally induced as well as spontaneously occurring OA.3
Unfortunately, none of the known MMP inhibitors (MMPIs) have been
successfully utilized as therapeutic agents so far. This was due to the lack
of selectivity for a specific isozyme, leading to heavy dose- and durationdependent
musculoskeletal side effects.4 Therefore, current drug
development strategies for treatment of OA are focused on selective
inhibition of MMP-13, although recent evidences suggest that other
MMPs, such as MMP-1, may also contribute to the collagen degradation
process.5 However, the design of a selective MMPI is not a trivial task, as
Pag. 7
MMPs share an high similarity in the overall three-dimensional fold and
many conserved amino acids exist in the inhibitor binding site, besides the
conserved catalytic zinc ion. The major structural difference observed
between the MMP enzymes resides in the relative size and shape of the S1’
subsite, which is located in proximity of the catalytic metal. From a
structural point of view, almost all MMPIs known so far are based on a
zinc-binding group (ZBG) and a hydrophobic portion protruding into the
hydrophobic S1’ subsite. These compounds behave as competitive
inhibitors since the ZBG can mimic one of the transition states occurring
during the substrate hydrolysis. Currently, two successful strategies to
confer selectivity of action to an MMP inhibitor are known: the first resides
in the proper modification of the P1’ substituent on MMPI to take
advantage of the differences between the diverse MMPs; the second is the
finding of an allosteric inhibitor,6 which binds tightly to the S1’ and S1’*
subsite without chelating the metal that is thought to contribute to the
promiscuous inhibition of multiple MMPs.Errore. Il segnalibro non è definito.c
Recently, as a result of the first strategy, it has been designed a Nisopropoxy-
arylsulfonamide-based hydroxamate inhibitor, which showed
low nanomolar activity for MMP-13 and high selectivity over some other tested MMPs.7 In parallel to further studies aiming to assess the activity of
this promising compound using in vivo models of OA, it has been decided
to seek for novel scaffolds as allosteric inhibitors on one hand, and as zincchelating
non-hydroxamate inhibitors on the other. In fact, a debate is still open on the advisability of using hydroxamates as ZBG due to toxicity and
metabolic stability issues.8,9
In this respect, we have taken advantage of the availability of several
MMP-13 crystal structures and have used two different in silico methods to
screen the Life Chemicals and the Maybridge databases, respectively.
Experimental tests of a limited selection of candidate compounds (60)
verified nine novel leads, structurally unrelated to the known MMPIs.
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