Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity.

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.