Identification of novel molecular scaffolds for the design of MMP-13 inhibitors through Virtual Screening Methods
Creators: name: La Pietra, Valeria
Publisher: name: Università degli Studi di Napoli Federico II
Year: 2010

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.