Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity.

Published on Jul 1, 2012in Molecular Informatics2.741
· DOI :10.1002/MINF.201100131
Federico Filomia2
Estimated H-index: 2
(University of Modena and Reggio Emilia),
Puneet Saxena9
Estimated H-index: 9
(University of Modena and Reggio Emilia)
+ 3 AuthorsMaria Cristina Menziani28
Estimated H-index: 28
(University of Modena and Reggio Emilia)
Sources
Abstract
The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1′ loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases.
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Over the last decade, there has been a large effort to target aggrecanases, which are responsible for the degradation of the aggrecan in the extracellular matrix of joints, in order to hopefully lead to new treatments for osteoarthritis. Only a few inhibitors have been effective in explants or rodent models and thus only a few have reached the clinic, none of which have proven to be effective. In this article, a survey of chemical series is described, covering historical and recent inhibitors an...
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